Deuterated domperidone compositions, methods, and preparation

ABSTRACT

Deuterated domperidone compositions, methods of synthesis, methods of use, and dosing formulations providing beneficial safety and other effects.

This application is a continuation of U.S. patent application Ser. No.15/639,431, filed Jun. 30, 2017, which is a continuation-in-part ofInternational Patent Application No. PCT/US2017/016334, filed Feb. 3,2017, which claims priority to U.S. Provisional Patent Application No.62/291,198, filed Feb. 4, 2016, each of which is expressly incorporatedby reference in its entirety.

Gastroparesis (GP) is a condition in which the motility of the stomachdoes not function or does not function properly, which prevents thestomach from emptying and interferes with digestion.

GP may be caused by damage to the vagus nerve, which regulates digestiveprocesses. Damage to the vagus nerve can be caused by diseases, such astype I or type II diabetes, or by stomach or small intestine surgery,and can limit the ability of the nervous system to send signals to thestomach muscles. Viral infections, certain medications, certain cancertreatments, scleroderma, nervous system disorders such as Parkinson'sdisease or multiple sclerosis, or hypothyroidism may also lead to orresult in GP.

Diagnosis of GP is typically by upper gastrointestinal (GI) endoscopy,computerized tomography (CT), enterography, magnetic resonanceenterography, upper GI series (x-ray), gastric emptying study, and/or abreath test. Symptoms of GP include nausea, vomiting, blood glucosealterations, abdominal pain, bloating, feelings of fullness after only afew bites, lack of appetite, weight loss, and malnutrition. Untreated GPcan lead to severe dehydration, malnutrition, hardening of undigestedfood in the stomach (bezoar), and erratic alternations in blood glucosethat can exacerbate diabetes.

Treatment of GP involves identifying and treating the underlyingpathology. GP arising from diabetes may be treated by dietaryalterations. GP may be treated with medications to stimulate the stomachmuscles, e.g., metoclopramide, erythromycin, and cisapride.Metoclopramide poses serious side effects, such as development ofmovement disorders or adverse interactions with other medications;erythromycin is susceptible to loss of efficacy as patient drugtolerance increases; and cisapride has limited accessibility.Medications to control nausea and vomiting include prochlorperazine,thiethylperazine, diphenhydramine, and ondansetron.

The symptoms of GP may be treated surgically, such as jejunostomy tubeplacement in the small intestine or gastric venting tube installation.For severe cases, a feeding tube may be inserted orally or nasally fordirect placement into the small intestine, or administered parenterally.

Domperidone is5-chloro-1-(1-[3-(2-oxo-2,3-dihydro-1H-benzo[d]imidazol-1-yl)propyl]piperidin-4-yl)-1H-benzo[d]imidazol-2(3H)-one,which has the following chemical structure:

As used herein unless expressly stated otherwise, any reference todomperidone includes pharmaceutically acceptable salts, esters,hydrates, solvates, prodrug forms, and derivatives of these, which isbroadly defined as domperidone compounds \that are modified or partiallysubstituted, examples include but are not limited to adding a singleatom, adding a reactive group, adding a functional group, forming adimer or multimer, conjugating to another molecule such as an antibody,etc.

Domperidone is an effective dopamine antagonist that does not readilycross the blood-brain barrier; as such, domperidone exhibits onlyminimal extrapyramidal side effects. Domperidone exhibits bothgastrokinetic and antiemetic activity, and exerts its gastrokineticaction by acting on the peripheral dopamine receptors in the stomach.Domperidone acts as a peripherally selective antagonist of the dopamineD2 and D3 receptors, and acts to block the dopamine receptors thatregister nausea. Domperidone can block dopamine receptors in the pyloricantrum and duodenum to increase motility in the upper GI tracts.Domperidone can also block dopamine receptors in the pituitary gland,which can increase the release of prolactin leading to increasedlactation, so is used to treat insufficient lactation. Domperidone hasbeen evaluated for use in treating nausea and vomiting, gastroparesis,Parkinson's disease, functional dyspepsia, insufficient lactation,pediatric reflux, gastroesophageal reflux disease, and other GI motilitydisorders or conditions.

SUMMARY

One embodiment is a therapeutic method to ameliorate any of all ofgastroparesis, nausea as a disorder separated from or associated withgastroparesis, vomiting as a disorder separate from or associated withgastroparesis, gastroesophageal reflux disease (GERD), and/or lactationinsufficiency, by administering domperidone deuterated with four (4)deuteriums in the unchlorinated aromatic ring (d₄) or six (6) deuteriumsin the linking propyl group (d₆). In one embodiment, domperidone-d₄ isadministered and is preferred over domperidone-d₆.

One embodiment is a method of making deuterated domperidone by reacting1,2-diaminobenzene having 0-4 deuteriums with a reactive carbonylspecies to produce a cyclic imide, reacting the cyclic imide with aprotecting group to produce a monoprotected cyclic imide, reacting themonoprotected cyclic imide with a 1,3-bifunctional propyl derivativehaving 0-6 deuteriums to produce an intermediate, reacting theintermediate with5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one, andremoving the protecting group either before or after reacting theintermediate with the5-chloro-1-(4-piperidinyl)-1,3-dihydro-2H-benzimidazol-2-one.

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1A-1B show a plasma profile of orally administered domperidone anddeuterated domperidone (FIG. 1A) and an analysis of the data shown inFIG. 1A (FIG. 1B).

FIG. 2 shows a representative drug release profile for an immediaterelease (IR) formulation and an extended release (XR) formulation.

FIG. 3 is a simulated plasma profile of deuterated domperidone from animmediate release portion and an extended release portion.

FIG. 4 shows a bilayer tablet with IR and ER layers.

FIG. 5 shows a trilayer tablet containing IR, ER, and a buffer layer.

FIG. 6 shows a tablet with an ER matrix and an IR coating.

FIG. 7 shows a capsule containing an IR tablet, a plug, and an ER tabletwith an osmotic system.

FIG. 8 shows a capsule containing IR and ER beads.

FIG. 9 shows a capsule containing IR and ER mini-tablets.

FIG. 10 shows a capsule containing IR and ER granules.

FIG. 11 shows a capsule containing an ER bead coated with an IR layer.

FIG. 12 shows a compressed tablet containing IR granules and a coated ERtablet embedded within the compressed tablet.

FIG. 13 shows a compressed IR tablet with an ER tablet embedded withinthe IR tablet.

FIG. 14 shows an ER tablet suspended in an IR liquid.

FIG. 15 shows a sachet containing a mixture of IR and ER granules orbeads.

FIG. 16 shows a sachet containing effervescent IR granules or beads andcoated ER granules or beads.

FIG. 17 shows a tablet with intermediate layers separated by bands.

FIG. 18 shows an orally disintegrating tablet containing coated,delayed/ER drug particles, beads or granules; the inset shows a drug ina polymer matrix.

FIG. 19 shows a capsule containing drug solution and coated, delayed/ERdrug particles, beads or granules.

FIG. 20 shows a softgel containing drug solution and coated, delayed/ERdrug particles, beads or granules.

FIG. 21 shows a liquid vehicle containing coated, delayed/ER drugparticles, beads or granules.

Like all drugs, the safety of domperidone is dependent upon itsmetabolism. A decreased metabolism renders a drug to have a longerresidence time in the body. Doses of domperidone required to treatgastroparesis, i.e., 10 mg administered three times a day for a total of30 mg, and up to 60 mg, can result in cardiac QT prolongation, which isdose related. Because of this effect it is not approved for thisindication in the United States, but is approved in Europe and Canada.

Domperidone is extensively metabolized; its major metabolic pathwaysproduce a 5-hydroxy form, an N-dealkylated form, and a hydroxylatedform. Methods that decrease domperidone metabolism would thus permit alower dose to be administered to achieve the same degree of efficacy ina patient, decreasing or eliminating the cardiac effect, and/ordecreasing the number of doses required to be administered, and/orproviding more consistent exposure that could enhance patient toleranceor efficacy.

Overall peak plasma levels of domperidone depend on its route ofadministration. Intramuscular (IM) and oral administration in a fastingindividual resulted in peak plasma levels at 10 min and 30 min postadministration; suppository administration resulted in peak plasmalevels at 1-2 hr post administration. Plasma concentrations were lowertwo hours after oral versus IM administration, likely due to hepaticfirst pass and gut wall metabolism. Peak plasma concentration was 40ng/ml after 10 mg IM injection, 20 ng/ml after oral ingestion of a 10 mgtablet, and 70-100 ng/ml oral ingestion of a 60 mg tablet or drops.Human plasma protein binding of 10 and 100 ng/ml tritiated domperidonewas 91.7% and 93.0% respectively. Bioavailability was relatively high at90% after IM injection, and relatively low at 13%-17% after oraladministration, even further decreased by antacid use because ofincreased stomach pH. RxMed: Pharmaceutical Information—MOTILIUM®,Janssen-Ortho, Domperidone Maleate.

Compared to the tritiated spiperone, the classic ligand used in centralnervous system (CNS) models, domperidone binds selectively andspecifically to striatal dopamine receptors. However, intravenous (IV)domperidone administration, even at high doses, does not displacelabeled spiperone in animal brain models because of its poor penetrationof the blood-brain barrier (Reddymasu et al., Am. J. Gastroenterology).Domperidone also has a high affinity for GI tissue; high concentrationsare found in esophagus, stomach, and small intestine. Domperidone blocksdopaminergic inhibition of GI transit. It is rapidly metabolized by theliver; after oral administration, 32% is excreted in urine and 66% isexcreted in feces. Elimination half-life is 7.5 hr in individuals thatare healthy, and about three times longer in individuals with renaldysfunction.

The efficacy of domperidone is based on its ability to increase theamplitude of esophageal motor function, enhance antral-duodenalcontractions, and better coordinate peristalsis across the pylorus withsubsequent acceleration of gastric emptying. Domperidone has effectiveantiemetic activity at the chemoreceptor trigger zone (CTZ) in thefourth ventricle of the brain but outside the blood-brain barrier. Ithas no cholinergic activity and is not inhibited by atropine.

Domperidone modulates gastric emptying of both solids and liquids, anddoes not alter gastric acid secretion, secretory volume, intragastricpH, or serum gastrin concentration.

At doses ranging from 10 mg to 30 mg orally, four times daily atone-half hour prior to meals and at bedtime, domperidone significantlyreduced gastrointestinal symptoms and hospitalizations fromgastroparesis, had a positive effect on the central control of vomitingand nausea, and accelerated emptying of a solid meal (Buckels et al.,Medscape General Medicine. 2003; 5(4) www.medscape.com).

One method to decrease domperidone metabolism is to administer adeuterated form of domperidone. Domperidone is extensively metabolized.Deuteration slows metabolism at key sites and routes of metabolism,producing higher efficacy with a lower dose. A deuterated form of asmall molecule increases its retention and thus decreases itsmetabolism, permitting a lower dose to be administered while achievingthe same efficacy as the higher dose without cardiac symptoms.

Deuterated domperidone can be synthesized or prepared by several routes.In general, any hydrogen in the chemical structure of domperidone can beeither hydrogen or deuterium. Beneficially, the sites of domperidonemetabolism, i.e., all non-substituted sites on the aromatic rings, canbe blocked by adding a commercially available deuterated alkyl halide,and the metabolite can be blocked by adding a commercially availabledeuterated alkyl halide for the propyl linker. This can considerablylower domperidone metabolism and improve its bioavailability.

Deuteration of a drug increases drug half-life, allowing for lessfrequent dosing as well as improved pharmacokinetics, i.e., absorption,distribution, and metabolism. The kinetic isotope effect (KIE) anddeuterium kinetic isotope effect (DKIE) are used to incorporatedeuterium into drugs. Gant, J. Med. Chem. (2014) 57, 3595-3611.

Deuterium forms more stable bonds with carbon than hydrogen. In somecases, deuterium substitution may provide altered drug metabolism.Altered drug metabolism may take many forms, e.g., improved metabolitestability, reduced formation of toxic metabolites, and/or increasedformation of active metabolites. Deuterated compounds may have anincreased half-life and increased systemic exposure compared tocorresponding non-deuterated forms. The increased half-life anddecreased metabolism may provide enhanced efficacy, tolerance, safety,and convenience so that lower doses of the deuterated form may yieldsimilar results as higher doses of the non-deuterated form. Deuteratedcompounds generally retain the biochemical potency and selectivity asthe corresponding non-deuterated forms. Any effects of deuteriumsubstitution on metabolic parameters are highly dependent on thespecific molecular positions at which deuterium is substituted forhydrogen.

Metabolic effects of deuterium substitution are not obvious orpredictable, even in compounds having similar chemical structures. Forexample, U.S. Publication No. 2009/0076010 discloses deuterium enrichedlamotrigine, an anticonvulsant. Deuteration is 14% to 100%, dependingupon the position of the hydrogen replaced by deuterium. Enrichmentmethods can be by proton exchange with deuterium, or by moleculesynthesis with deuterium enriched starting materials. U.S. PublicationNo. 2009/0131485 discloses deuterium enriched pirfenidone, an inhibitorof collagen production blocking fibroblast proliferation and stimulationin response to cytokines, investigated for treating neurofibromatosis,multiple sclerosis, and other fibroid related diseases. It disclosessynthesis methods and isotopes, and methods for enhancingbioavailability and dosing. Deuterated pirfenidone has a half-liferanging from 110%-140% or more, depending on the degree of deuteration.The effective amount ranges from 80% to 40% or less compared tonon-deuterated forms. U.S. Publication no. 2011/0160253 disclosesdeuterium enriched tizanidine, a benzothiazole that acts as a centrallyacting α₂-adrenoceptor agonist used to manage muscle hypertonia andmuscle spasticity associated with multiple sclerosis, spinal cordinjury, etc. It discloses deuteration methods; enrichment ranges from52.5%-99.5% and pharmaceutical compositions, effective amounts, anddoses are discloses. Harbeson and Tung, MECHEM NEWS No. 2 May 2014, 8-22disclose deuterium substitution can improve safety, efficacy, and/ortolerance of a therapeutic agent.

Deuterated drugs have been used in non-clinical settings and asmetabolic and pharmacokinetic probes, but none are approved as a humantherapeutic. Depending on the desired deuteration sites, D₂O may beexchanged directly into the finished drug compounds, or into reagentsused for synthesizing drugs. Deuterium has low systemic toxicity.Deuterium gas may be used as a starting material for incorporatingdeuterium. Catalytic deuteration of olefinic and acetylenic bonds canrapidly incorporate deuterium. Metal catalysts such as Pd, Pt, and Rh inthe presence of deuterium gas can be used to directly exchange deuteriumfor hydrogen in functional groups containing hydrocarbons. Deuteratedregents and synthetic building blocks are commercially available. Theshape and size of a molecule is very similar in a deuterated versusnon-deuterated form. Minor physical property changes in partially orfully deuterated compounds are reduced hydrophobicity, decreased acidityof carboxylic acids and phenols, and increased basicity of amines butmost of these small differences have negligible effects on biochemicalpotency or target selectivity. Binding isotope effects are well knownand can contribute either positively or negatively to a measureddeuterium kinetic isotope effect. There are also reduced metabolic ratesand metabolic switching, where the ratio of metabolites is changed.Changes in an individual's exposure to parent drug and metabolites canhave ramifications on pharmacodynamics, tolerance, and efficacy of thedeuterated drug. Deuteration reduces formation of undesired or toxicmetabolites, as well as enhancing formation of desired metabolites. Anexample of positive effects of metabolic shunting is deuteratednevirapine that resulted in reduced rash incidence and severity, andeach of deuterated efavirenz, indilon, and odanacatib resulted in lowerside effects with enhanced efficacy in a rat model. Deuteratedrofecoxib, also known as BDD-11602, had an improved pharmacokineticprofile in a rat model compared to non-deuterated rofecoxib. Deuteratedtelaprevir, an inhibitor of hepatitis C viral NS3-4A protease, had a 13%increase in epimerization rate, but negligible effect on antiviralactivity. Deuterated effects on the metabolic profile of any particulardrug are not predictable, although there is potential for improvedsafety, tolerability, efficacy, and dosing.

One method to decrease domperidone metabolism is to administer adeuterated form of domperidone. A deuterated form of a small moleculewill increase its retention and thus decrease its metabolism, permittinga lower dose to be administered but achieving the same efficacy as thehigher dose, but without the cardiac symptoms. Domperidone isextensively metabolized so deuteration slows metabolism at key sites andkey routes of metabolism, producing higher efficacy with a lower dose.This is demonstrated in FIGS. 1A and 1B, subsequently described, wherethe area under the curve is higher for the deuterated compounds. Table1, subsequently described, shows the reduction in metabolite formationfor compound 2 over a 60 min time period.

Compound 1 below shows a general deuterated form of domperidone whereR=either H or D independently allowing for 1 to 10 deuterium to bepresent. Any and all permutations of deuterated sites may be usedwithout limitation. The most significant sites for deuteration are thearomatics as shown, and the methylene of the alkyl linker alpha to thepiperidine nitrogen. The primary hydroxylated metabolites are in thisaromatic ring and the presence of deuterium will reduce the rate atwhich these metabolites are formed. The dealkylation metabolic pathwayinvolves those alpha protons via an elimination mechanism of theN-oxide; deuterium is slower to eliminate thus slowing this route ofmetabolism. In one embodiment, deuterated compounds of compound 1 areused and/or prepared as described herein.

Domperidone may be deuterated at any hydrogen site. In compound 2,deuteration of the aromatic H atoms, of the unsubstituted aromatic ring,yields domperidone-d₄. Additional deuteration of H of one or moremethylene sites in the linking propyl group, yields compound 3domperidone-d₆ or domperidone-d₈ (not shown) or compound 5domperidone-d₁₀. It is also possible to deuterate H at one or more ofthe methylene sites while retaining H at the aromatic sites. Forexample, deuteration of H of one methylene group yields compound 4domperidone-d₂, and deuteration of H of two methylene groups yieldsdomperidone-d₄ (not shown).

In one embodiment, any of compounds 2, 3, and/or 4 are administered. Anyof compounds 2, 3, and 4 impact reducing the rate of metabolism and arepreferred.

Raw materials with deuterium only at the alpha methylene are likely moreexpensive and less readily available than those where the propyl groupis fully deuterated.

Compound 2 is used and is preferred in one embodiment.

Compound 5 is used and is preferred in one embodiment.

Compounds 2 and 5 are used and are preferred in one embodiment.

Compounds 2, 5, and 6 are used in one embodiment.

In one embodiment, compounds containing 1-8 deuteriums in the cyclohexylamine, such as compound 13, are used.

Scheme 1 shows a general synthesis for preparing various deuterateddomperidone compounds generally shown as compound 1. Synthesis is basedon the non-deuterated analog in Vandenberk U.S. Pat. No. 4,066,772. Theprocess begins with 1,2-diaminobenzene substituted with 0 to 4deuteriums on the aromatic ring. The imide is closed using ethylchlorformate, or another similar reactive carbonyl species, in anappropriate solvent such as, but not limited to, an ether such astetrahydrofuran (THF), halocarbons such as dichloromethane, ketones suchas acetone, hydrocarbons such as heptane, and amides such asN,N-dimethylformamide (DMF). Compound 8 is then monoprotected with anappropriate protecting group such as, but not limited to, carbamates,sulfonamides, and vinyl alkyls. The second nitrogen is then reacted witha 1,3-bifunctional propyl derivative containing 0 to 6 deuteriums. Thefunctionality can be independently either halogen (Br, Cl, I), hydroxyl,or an appropriate leaving group such as tosylate or mesylate. In apreferred embodiment, the two groups are differentiated. The remainingleaving group X of compound 10 may be optionally exchanged for a morereactive species, e.g., if X is chloride the chloride may be exchangedfor an iodide, or if X is a tosylate the tosylate may be exchanged for atrifluoromethanesulfonate (triflate). Protecting group P may also beremoved in this step.

Intermediate 10 or 12 is then reacted with compound 14 using either abase or other appropriate coupling procedure. Compound 14 is preparedusing methods known in the art. Removal of the protecting group yieldsthe desired deuterated domperidone derivative 1. Alternatively,protecting group P may be removed prior to alkylation with 14. Allcompounds are prepared in accord with this general scheme using theappropriately substituted deuterated starting materials.

Synthesis of compound 13 follows known methods for non-deuteratedmaterial but beginning with a deuterated 4-aminopiperidine derivative.

Scheme 2 shows an alternative synthesis for deuterated domperidone. Anappropriately deuterated 1,2-aminobenzene is reacted with tetraethylorthocarbonate in the presence of a catalyst and in a suitable solvent,resulting in compound 15. In one embodiment the catalyst is acetic acid.In one embodiment the solvent is ethanol. In another embodiment thecatalyst is propionic acid. In another embodiment the solvent isisopropyl alcohol. In embodiments, an appropriate organic or inorganicacid in an appropriate solvent may be used, non-limiting examplesinclude an ether or alcohol. A 1,3-bifunctional propyl derivativecontaining 0-6 deuteriums is then reacted with the protonated nitrogen Nof imide 15 in the presence of base and in a solvent to provide compound16. In one embodiment the base is K₂CO₃. In one embodiment the solventis methyl isobutyl ketone (MIBK). In another embodiment the base issodium hydride. In another embodiment the solvent is dimethylformamide(DMF). In embodiments, organic bases such as N,N-diisopropylethylamine(DIPEA), n-butyllithium (nBuLi), lithium bis(trimethylsilyl)amide(LHMDS), etc., or inorganic bases such as potassium hydride as examplesmay be used. Substitution of compound 14 and deprotection of thebenzimidazole results in deuterated domperidone 1.

The Scheme 2 synthesis of deuterated domperidone involves only threesteps, each of which results in high yields of product. The overallyield of deuterated domperidone from Scheme 2 is greatly improved overthe yield of deuterated domperidone from Scheme 1.

FIG. 1 shows decreased metabolism caused by deuteration of domperidone,where the area under the curve of rat plasma levels of orallyadministered domperidone is higher for the deuterated domperidonecompounds 2 and 6 relative to undeuterated domperidone. The table belowshows reduced metabolite formation in human hepatocytes for domperidonecompounds 2 and 6 over a 60 min. time period relative to undeuterateddomperidone.

TABLE 1 Percentage of metabolite formation in human hepatocytes % ofoxidative % of sulfonated Sample metabolite metabolite Domperidone 0 min0.08 0 Domperidone 30 min 2.64 0.23 Domperidone 60 min 3.79 0.37Compound 2 0 min 0 0 Compound 2 30 min 0.15 0.01 Compound 2 60 min 0.210.02 Compound 6 0 min 0.03 0 Compound 6 30 min 1.42 0.13 Compound 6 60min 1.91 0.22

Another method to decrease domperidone metabolism is to administer thedrug sublingually, so that the active is immediately available in thecirculatory system and bypasses the digestive system where metabolismoccurs. A sublingual form of domperidone or a deuterated domperidone,formulated as a tablet, film, or other suitable formulation, can beadministered at a lower dose but with comparable efficacy as an orallyadministered form. The pharmacokinetics of domperidone, particularly itst_(1/2), pK_(a), log P, and K_(d) make it favorable for sublingualadministration.

Another method to decrease domperidone metabolism is to administer theactive in a particulate form providing increased surface area. Forexample, domperidone or a deuterated domperidone can be formulated asmicroparticles or nanoparticles. Using the biopharmaceuticsclassification system (BCS), it is known that Class II drugs have highpermeability and low solubility, such that their bioavailability islimited by their rate of solvation. In this embodiment, themicroparticle or nanoparticle or other formulation providing increasedsurface area increases bioavailability by increasing the rate ofsolvation, and can be administered at a lower dose but with comparableefficacy as an orally administered form.

It will be appreciated that other formulations may achieve similar orthe same results, e.g., using a spray formulation, a powder, a thinfilm, etc., and using either domperidone or a deuterated domperidone.

It will be appreciated that the embodiments may be used in combination.As one example, a microparticle or nanoparticle form of domperidone maybe applied to or incorporated in a thin film and administeredsublingually. As another example, a deuterated form of domperidone maybe formulated as a microparticle or nanoparticle, and may in someembodiments be administered sublingually, e.g., in or on a thin film, asa spray, etc. In these combination examples, the dose of domperidone maybe further reduced due to its increased bioavailability and decreasedmetabolism.

The following preparations and formulations can be used for eitherdeuterated or non-deuterated forms of domperidone.

Nanoparticles can be prepared using dry milling or wet milling. Examplesof dry milling processes include those disclosed in U.S. PatentPublication Nos. 2013/0209569, 2010/0092563, 2014/0287039, 2014/0200276,2014/0194487, 2014/0255494, 2013/0243854, 2014/0248359, 2014/0256781,2014/0302127, 2014/019395, 2014/0220121, 2012/0135048, 2014/0326812,2009/0028948, and U.S. Pat. Nos. 9,089,471; 9,095,496; 9,180,096;9,173,854; 9,017,721; 8,679,544; 8,999,387; 8,734,847; 8,992,982;9,180,096; 9,186,328; 8,735,450; and 8,808,751. An exemplary wet millingprocess is disclosed in U.S. Pat. No. 9,107,827. Any of theseformulations, including but not limited to thin films, tablets, sprays,solutions, etc. include a sublingual dosage form.

Domperidone, either deuterated or non-deuterated forms, can beadministered through the skin, i.e., transdermally. Absorption throughthe skin, also referred to as percutaneous delivery, transdermaldelivery, or dermal delivery, transports domperidone from the outerepidermal surface both into the skin and into the systemic circulation.The epidermal surface is the primary route of absorption in transdermaldelivery, although small amounts of agent may also be transferredthrough hair follicles or glands. From the epidermal starting surface,the agent passes through seven epidermal layers prior to entering thedermis, from which the agent enters the circulatory and/or lymphaticsystems. The stratum corneum is the outermost or surface exposure skinlayer, and is the rate-limiting barrier for entry of an external agent,thus the rate of passage through the stratum corneum determines overallabsorption. The primary stratum corneum components are the lipophiliccompounds cholesterol, cholesterol esters, and ceramides. Agents withgreater lipid-solubility thus more rapidly penetrate the stratum corneumand achieve systemic exposure, compared to agent with lesslipid-solubility, but the majority of all agents penetrate the stratumcorneum to some extent. The solubility of domperidone is related to itspH; domperidone is a weak base, pK_(a) 7.89, with limited solubility inwater having a lipid to water ratio of 3.90.

The health and integrity of the stratum corneum affects agentpenetration. For example, agents such as strong acids that injure ordisrupt the stratum corneum composition are rapidly absorbed. Skindamage due to burns, abrasions, wounds, and disease also affectabsorption. Some solvents, e.g., dimethyl sulfoxide (DMSO) increase thepermeability of stratum corneum, acting as carriers and thus used aspenetration enhancers or facilitators. Some surfactants, e.g., sodiumlauryl-sulfate, increase skin penetration of water soluble agents,possibly in increasing skin permeability of water.

Transdermal delivery may be achieved by topical administration,environmental exposure, and/or injection. Absorption through the skindepends on agent factors including but not limited to concentration,molecular weight, and lipophilic/hydrophilic nature or solubility, butalso contact duration, physical condition of the skin, surface exposed,and the presence or absence of hair follicles on the exposed surface.For example, agent absorption from various skin surfaces occursaccording to the following scheme from quickest to slowest:scrotal>forehead>axilla>scalp>back>abdomen>palm/foot undersurface due tothe keratinized, stratified squamous cell layer of stratum corneium thatfunctions to prevent water loss from underlying tissues.

Dermal application of domperidone may permit more localized therapy, andmay avoid or minimize first pass hepatic metabolism. Dermaladministration may thus achieve higher systemic concentrations. Dermaladministration formulations include patches, lotions, liniments,ointments, tinctures, creams, powders, aerosols, gels, etc. Patches maybe controlled release and may permit domperidone release for 7 days, inone embodiment. Patches may include a penetration enhancer, which mayfacilitate or in some cases be important for delivery. In a transdermalpatch, domperidone or a prodrug form of domperidone is present in as afree base and/or salt.

The amount of domperidone that is absorbed by transdermal applicationcan be measured directly or indirectly using methods known in the artand as subsequently described. Even with in vivo studies, speciesdifferences may be notable. Moreover, the different formulationspreviously described may affect concentrations delivered. Directconcentration measurement may be performed using in vivo methods bydirectly applying domperidone to the skin and measuring domperidone inblood and urine at set times, then plotting the results on a graph andmeasuring the area under the curve (AUC). Ex vivo methods may be usedbecause the permeability of the stratum corneum is not significantlychanged when skin is carefully removed. Chamber studies, using anyformulation of domperidone (e.g., films, patches, lotions, etc., seee.g., Basu, IRJP 3 (2012)134-45; Madishetti et al. Dam 18 (2010) 221-29;Khan et al. Bull. Pharm. Res. 2 (2012) 15-21) applied to one surface ofan isolated skin sample and its concentration measured on the othersurface of the same sample, are known, e.g., isolated perfused porcineflap (Riviere, Fundam Appl Toxicol 7 (1986) 444-53). In vitro methodsinclude static and flow-through diffusion cells, examples of which areFranz cells and Bronaugh cells (Bronaugh and Stewart, J. Pharm. Sci, 74(1985) 64-67), respectively. The static Franz cell apparatus has anupper donor chamber and a lower receiving chamber containing a fluid,with the upper and lower chambers separated by the skin sample as amembrane. The receiving fluid in the lower chamber is typically bufferedsaline with a known amount of protein, e.g., bovine serum albumen or abiological fluid, and is in contact with the skin membrane. In use, aknown volume and concentration of domperidone in a vehicle is applied tothe upper chamber and permeates through the skin membrane, diffusing orotherwise entering into the receiving fluid in the lower chamber. Thisreceiving fluid is sampled, typically via a sampling port that alsoreplaces the fluid volume removed, and analyzed at regular intervals todetermine the amount of domperidone that permeated the skin membrane.The flow-through Bronaugh cell apparatus is similar to the Franz cellapparatus, but uses a flow-through system in the lower chamber fromwhich samples are obtained and analyzed continuously rather than at settime points.

Methods for domperidone transmucosal delivery are disclosed in U.S.Publication No. 2010/0255096. Mucoadhesive delivery technologies providesafe and efficacious delivery of an agent such as domperidone. Thesemucoadhesive delivery technologies include all methods of diffusion inthe oral mucosa: passive diffusion including trans-cellular (throughcells) and para-cellular (through lipid rich domains around the cells),carrier mediated transport, and endocytosis/exocytosis for activecellular uptake and excretion by the endocytic pathway.

Mucous membranes, mucosae, line body cavities that are either externallyexposed to the environment or are internal organs. The oral mucosa isthe mucous membrane lining the inside of the mouth and consists ofstratified squamous epithelium (oral epithelium) and an underlyingconnective tissue (lamina propria). It can be further divided into threemain categories based on function and histology: masticatory mucosa ofkeratinized stratified squamous epithelium found on the dorsum of thetongue, hard palate and attached gingiva; lining mucosa ofnon-keratinized squamous epithelium found almost everywhere else in theoral cavity including the buccal mucosa which lines the cheeks, thelabial mucosa which is the inside lining of the lips, and the alveolarmucosa which is the mucosa between the gums and the buccal/labialmucosa; and specialized mucosa in the regions of the taste buds onlingual papillae on the dorsal surface of the tongue. Bioadhesivepolymers adhere to any moist surface, thus a mucoadhesive/bioadhesiveformulation adheres to both saliva-moistened keratinized andnon-keratinized mucosa.

Exemplary transdermal formulations are provided below, all percentagesare weight/weight. While the following formulations list domperidone,one of ordinary skill in the art is aware that domperidone may refer toeither domperidone or deuterated domperidone.

Formulation 1 Domperidone 1% Domperidone 1% Propylene carbonate 5%Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100% Formulation2 Formulation 8 Domperidone 1% Domperidone 1% Diethyl sebacate 15% TRANSCUTOL ® 20%  Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to100% Formulation 3 Formulation 9 Domperidone 1% Domperidone 1%Diisopropyl adipate 20%  Lauric diethanolamide 15%  Dimethyl sulfoxideqs to 100% Dimethyl sulfoxide qs to 100% Formulation 4 Formulation 10Domperidone 1% Domperidone 1% Dimethyl isosorbide 15%  PEG 400 20% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100% Formulation5 Formulation 11 Domperidone 1% Domperidone 1% Dipropylene glycol 10% Cocamide DEA 5% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to100% Formulation 6 Formulation 12 Domperidone 1% Domperidone 1% Hexyleneglycol 12%  Oleic acid 20%  Dimethyl sulfoxide qs to 100% Dimethylsulfoxide qs to 100% Formulation 7 Formulation 13 PEG-7 methyl ether20%  Domperidone 1% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qsto 100% Formulation 14 Formulation 20 Domperidone 1% Domperidone 1%Polysorbate 80 15%  Lauryl lactate 5% Dimethyl sulfoxide qs to 100%Dimethyl sulfoxide qs to 100% Formulation 15 Formulation 21 Domperidone1% Domperidone maleate 1% BRIJ ® L23 69 LQ 5% Dimethyl sulfoxide qs to100% Dimethyl sulfoxide qs to 100% Formulation 22 Formulation 16Domperidone maleate 1% Domperidone 1% Diethyl sebacate 15%  BRIJ ® S 20So MH 5% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100%Formulation 23 Formulation 17 Domperidone maleate 1% Domperidone 1%Diisopropyl adipate 20%  BRIJ ® L4 LQ 5% Dimethyl sulfoxide qs to 100%Dimethyl sulfoxide qs to 100% Formulation 24 Formulation 18 Domperidonemaleate 1% Domperidone 1% Dimethyl isosorbide 15%  Isopropyl palmitate8% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100%Formulation 25 Formulation 19 Domperidone maleate 1% Domperidone 1%Dipropylene glycol 10%  Levulinic acid 5% Dimethyl sulfoxide qs to 100%Formulation 26 Formulation 32 Domperidone maleate 1% Domperidone maleate1% Hexylene glycol 12%  Oleic acid 20%  Dimethyl sulfoxide qs to 100%Dimethyl sulfoxide qs to 100% Formulation 27 Formulation 33 Domperidonemaleate 1% Domperidone maleate 1% Propylene carbonate 5% PEG-7 methylether 20%  Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100%Formulation 28 Formulation 34 Domperidone maleate 1% Domperidone maleate1% TRANSCUTOL ® 20%  Polysorbate 80 15%  Dimethyl sulfoxide qs to 100%Dimethyl sulfoxide qs to 100% Formulation 29 Formulation 35 Domperidonemaleate 1% Domperidone maleate 1% Lauric diethanolamide 15%  BRIJ ® L2369 LQ 5% Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100%Formulation 30 Formulation 36 Domperidone maleate 1% Domperidone maleate1% PEG 400 20%  BRIJ ® S 20 So MH 5% Dimethyl sulfoxide qs to 100%Dimethyl sulfoxide qs to 100% Formulation 31 Formulation 37 Domperidonemaleate 1% Domperidone maleate 1% Cocamide DEA 5% BRIJ ® L4 LQ 5%Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100% Domperidonemaleate 1% Formulation 38 Isopropyl palmitate 8% Domperidone maleate 1%Dimethyl sulfoxide qs to 100% DURO-TAK ® 387-2516 75%  Formulation 39BRIJ ® S 20 So MH 5% Domperidone maleate 1% Dimethyl sulfoxide qs to100% Levulinic acid 5% Formulation 45 Dimethyl sulfoxide qs to 100%Domperidone maleate 1% Formulation 40 DURO-TAK ® 387-2516 75% Domperidone maleate 1% BRIJ ® L4 LQl 5% Lauryl lactate 5% Dimethylsulfoxide qs to 100% Dimethyl sulfoxide qs to 100% Formulation 46Formulation 41 Domperidone maleate 1% Domperidone maleate 1% DURO-TAK ®387-2516 60%  DURO-TAK ® 387-2516 79%  Diethyl sebacate 20%  Dimethylsulfoxide qs to 100% Dimethyl sulfoxide qs to 100% Formulation 42Formulation 47 Domperidone maleate 1% Domperidone maleate 1% DURO-TAK ®387-2516 60%  DURO-TAK ® 387-2516 60%  TRANSCUTOL ® 20 Diisopropyladipate 20%  Dimethyl sulfoxide qs to 100% Dimethyl sulfoxide qs to 100%Formulation 43 Formulation 48 Domperidone maleate 1% Domperidone maleate1% DURO-TAK ® 387-2516 68%  DURO-TAK ® 387-2516 70%  Hexylene glycol12%  Levulinic acid 10%  Dimethyl sulfoxide qs to 100% Dimethylsulfoxide qs to 100% Formulation 44 Formulation 49 DURO-TAK ® 387-251670%  Domperidone maleate 1% Lauryl lactate 10%  DURO-TAK ® 387-2516 55% Dimethyl sulfoxide qs to 100% BRIJ ® S 20 So MH 5% Formulation 50Diisopropyl adipate 20%  Domperidone maleate 1% Dimethyl sulfoxide qs to100% DURO-TAK ® 387-2516 60%  Formulation 55 Polysorbate 80 20% Domperidone maleate 1% Dimethyl sulfoxide qs to 100% DURO-TAK ® 387-251665%  Formulation 51 BRIJ ® S 20 So MH 5% Domperidone maleate 1% Lauryllactate 10%  DURO-TAK ® 387-2516 55%  Dimethyl sulfoxide qs to 100%BRIJ ® S 20 So MH 5% Formulation 56 TRANSCUTOL ® 20%  Domperidonemaleate 1% Dimethyl sulfoxide qs to 100% DURO-TAK ® 387-2516 54% Formulation 52 TRANSCUTOL ® 20%  Domperidone maleate 1%  BRIJ ® L4LQ 5%DURO-TAK ® 387-2516 63%  Dimethyl sulfoxide qs to 100% BRIJ ® S 20 So MH5% Formulation 57 Hexylene glycol 12%  Domperidone maleate 1% Dimethylsulfoxide qs to 100% DURO-TAK ® 387-2516 62%  Formulation 53 Hexyleneglycol 12%  Domperidone maleate 1% BRIJ ® L4 LQ 5% DURO-TAK ® 387-251670%  Dimethyl sulfoxide qs to 100% BRIJ ® S 20 So MH 5% Formulation 58BRIJ ® L4 LQ 5% Domperidone maleate 1%  Dimethyl sulfoxide qs to 100%DURO-TAK ® 387-2516 54% Formulation 54 BRIJ ® L4 LQ 5% Domperidonemaleate 1% Diethyl sebacate 20%  Diethyl sebacate 20%  Dimethylsulfoxide qs to 100% BRIJ ® L4 LQ 5% Formulation 63 Dimethyl sulfoxideqs to 100% Domperidone maleate 5% Formulation 59 TRANSCUTOL ® 40% Domperidone maleate 1% BRIJ ® L4 LQ 5% DURO-TAK ® 387-2516 54%  Diethylsebacate 20%  Diisopropyl adipate 20%  Dimethyl sulfoxide qs to 100%BRIJ ® L4 LQ 5% Formulation 64 Dimethyl sulfoxide qs to 100% Domperidonemaleate 10%  Formulation 60 TRANSCUTOL ® 35%  Domperidone maleate 1%BRIJ ® L4 LQ 5% DURO-TAK ® 387-2516 64%  Diethyl sebacate 20%  Lauryllactate 10%  Dimethyl sulfoxide qs to 100% BRIJ ® L4 LQ 5% Formulation65 Dimethyl sulfoxide qs to 100% Domperidone maleate 1% Formulation 61DURO-TAK ® 387-2516 59%  Domperidone maleate 1% TRANSCUTOL ® 5%DURO-TAK ® 387-2516 54%  BRIJ ® L4 LQ 5% TRANSCUTOL ® 10%  Diethylsebacate 5% BRIJ ® L4 LQ 5% Limonene 5% Diethyl sebacate 10%  Dimethylsulfoxide qs to 100 Dimethyl sulfoxide qs to 100% Formulation 66Formulation 62 Domperidone maleate 1% Domperidone maleate 1% DURO-TAK ®387-2516 74%  TRANSCUTOL ® 40%  TRANSCUTOL ® 5% Limonene 5% BRIJ ®L4LQ5% Dimethyl sulfoxide qs to 100% Diethyl sebacate 5% Formulation 67Dimethyl sulfoxide qs to 100% Domperidone maleate 1% Formulation 69DURO-TAK ® 387-2516 64%  Domperidone maleate 1% TRANSCUTOL ® 5%DURO-TAK ®387-2516 59%  BRIJ ® L4LQ 5% TRANSCUTOL ® 5% Diethyl sebacate5% BRIJ ® L4LQ 5% Dimethyl sulfoxide qs to 100% Diethyl sebacate 5%Formulation 68 Limonene 5% Domperidone 1% Dimethyl sulfoxide qs to 100%DURO-TAK ® 387-2516 64% 

One embodiment is a composition and method for treating gastroparesiswith domperidone or deuterated domperidone or pharmaceuticallyacceptable salts thereof, provided in a sublingual dosage form. Examplesof sublingual dosage forms include sublingual tablets, biocompatiblethin films, and sublingual sprays. For example, sublingual tablets couldbe prepared as rapidly disintegrating tablets (RDT). RDT are soliddosage forms containing a medicament that rapidly (≤30 seconds)disintegrates when placed on or under the tongue, i.e., upon salivacontact. Formulation of domperidone or deuterated domperidone in RDTenables oral domperidone administration without water or withoutchewing. Commercially available RDT technologies are lyophilizedtablets, compressed tablets, molded tablets, spray dried powders, thinfilms, and sugar-floss systems (McLaughlin et al., PharmaceuticalTechnology, Supplement to September 2009 issue).

One embodiment is a composition and method for treating gastroparesiswith domperidone or deuterated domperidone or pharmaceuticallyacceptable salts thereof, in a biocompatible nanoparticle formulation.In one embodiment, domperidone or deuterated domperidone is formulatedfor topical application. In one embodiment, domperidone or deuterateddomperidone is formulated in and/or on a film, either directly orindirectly. For example, domperidone or deuterated domperidone may beformulated to be contained in the film matrix, or may be formulated as alayer of the film, or may be formulated in a vehicle that is applied tothe film. The vehicle may be a suspension, foam, emulsion, etc. In oneembodiment, domperidone or deuterated domperidone is formulated in atopically applied foam. In one embodiment, domperidone or deuterateddomperidone is formulated in, on, or associated with a nanoparticle. Inother embodiments, domperidone or deuterated domperidone is formulatedas a solid tablet, or in a liquid such as a syrup, suspension, solution,or emulsion, or as an injectable.

Thin films formulations include, but are not limited to, those disclosedin U.S. Patent Publication Nos. 2014/0271788, 2014/0272220,2014/0271787, 2014/0163060, 2014/0070440, 2014/0017299, 2013/0333831,and 2013/0220526.

Nanoparticle formulations include any nanosized structure that includes,but is not limited to, quantum dots including graphene quantum dots,graphene-oxide quantum dots, and graphene-zinc oxide quantum dots,nanotubes including graphene nanotubes and/or carbon nanotubes,fullerenes, buckyballs, dendrimers, liposomes, aptamers, micelles, etc.

The formulations provide ready patient compliance and optimal dosedelivery for treating the symptoms of gastroparesis. It will beappreciated that other gastric motility disorders may also be treatedwith the disclosed compositions and methods. “Pharmaceuticallyacceptable” refers to properties and/or substances that are acceptableto the patient from a pharmacological/toxicological vantage, and to themanufacturing pharmaceutical chemist from a physical/chemical vantageregarding composition, formulation, stability, patient acceptance, andbioavailability.

A pharmaceutically acceptable salt includes salts with apharmaceutically acceptable acid or base, e.g., inorganic acids, e.g.,hydrochloric, sulfuric, phosphoric, diphosphoric, hydrobromic,hydroiodic and nitric acid and organic acids, for example citric,fumaric, maleic, malic, mandelic, ascorbic, oxalic, succinic, tartaric,benzoic, acetic, methanesulphonic, ethanesulphonic, benzenesulphonic,cyclohexylsulfamic (cyclamic) or p-toluenesulphonic acid.Pharmaceutically acceptable bases include alkali metal, e.g. sodium orpotassium, and alkali earth metal, e.g. calcium or magnesium,hydroxides, and organic bases, e.g., alkyl amines, arylalkyl amines andheterocyclic amines.

The formulations can be administered orally in solid form, such as atablet, capsule, lozenge, or gum, or in liquid form as a syrup,emulsion, solution, or suspension in an aqueous or non-aqueous vehicle.In solid forms, formulations may be controlled release or rapiddissolution for rapid onset. The formulations can also be administeredby injection, which can be subcutaneous, intradermal, intramuscular,intravenous, or other injection methods. Formulations for administrationthrough injection can include suspensions, solutions, or emulsions inaqueous or non-aqueous vehicles. Other formulations can be deliveredintranasally, vaginally, rectally, or transdermally. Formulations canalso be delivered transmucosally. The preparation can be administeredonce a day to four times a day.

In one embodiment, a domperidone or deuterated domperidone solution orsuspension is put into a blister pack and lyophilized to prepare a unitdose. A lyophilized suspension may include regular particles, micronizedparticles, or nanoparticles. The following lyophilized technologyplatforms include ZYDIS® (Catalent), LYOC™ (Cephalon), PHARMAFREEZE®(SPI Pharmaceuticals), and QUICKSOLV® (Janssen).

For a lyophilized RDT product for sublingual administration domperidoneor deuterated domperidone, as the active pharmaceutical ingredient(API), is dispersed in a matrix of a polymeric structure former, e.g.,gelatin, and a saccharide, typically mannitol, dissolved in water. Inthe finished product, the glassy amorphous structure of the polymericcomponent imparts strength and resilience while retaining someflexibility. The specific gelatin grade and its associated dissolutioncharacteristics ensure a smooth, rapid melt in the mouth. Mannitolcrystallizes during freezing, providing an elegant appearance andrigidity and ensuring that the product is robust to handling andtransport. Mannitol is readily soluble so also improves texture, taste,and mouthfeel. Domperidone or deuterated domperidone may be dissolved inthe matrix or dispersed to form a homogenous suspension for dosing.Liquid dosing ensures good dose uniformity and accommodates extremelylow-dose strengths, e.g., micrograms. Suspension dose strengths up to400 mg can be accommodated, and domperidone or deuterated domperidone istypically micronized. Particle size is a consideration becauseparticles >50 μm may feel gritty. Solution products, due to depressionof freezing point by soluble API, can accommodate dose strengths up to60 mg. Both solution and suspension based products use finely disperseddomperidone or deuterated domperidone in the dried unit, contributing torapid dispersion and smooth mouthfeel. Other excipients, as subsequentlydescribed, may be included. Domperidone or deuterated domperidone isdispensed into preformed blister packs and rapidly cooled by liquidnitrogen for rapid freezing.

Freezing results in a network of ice crystals that are sublimed duringlyophilization to produce a highly porous structure. The matrixcomponents maintain the structure of the dried unit, but on contact withmoisture, the high porosity results in rapid water penetration. Thematrix quickly dissolves, resulting in fast disintegration (<10seconds).

After freezing, the domperidone or deuterated domperidone islyophilized, dosed, and dried in blister packs which are sealedproviding physical and environmental protection. The product slightlyadheres to the pack, resulting in minimum movement of the product withinthe blister pockets to ensure robustness during transport. The productis a wafer-like structure but of minimum friability and of sufficientstrength to be removed from the pack without breakage.

The lyophilized RDT formulations' wafer-like structure and high porosityreflect that water is typically the major component of the dosingformulation, so the weight of the dried product is significantly reducedand often dictated primarily by the dose of domperidone or deuterateddomperidone. The recommended 500 mg weight limit for RDT is likelyapproached for the highest domperidone or deuterated domperidone dose inlyophilized formulations, offset by its rapid disintegration.

After administration and rapid dispersion on or under the tongue, thelyophilized formulation effectively reverts to the original domperidoneor deuterated domperidone solution or suspension. The lyophilized RDTtablet thus provides the convenience of a solid oral dosage form withthe benefits of a solution/suspension product, suitability for buccaland sublingual uptake to enhance bioavailability directly into thesystemic circulation and avoid first-pass metabolism to minimizeundesirable metabolites, and physical and chemical stability with shelflife comparable to conventional tablets, i.e., 2-5 years.

QUICKSOLV® starts with an aqueous domperidone or deuterated domperidoneand matrix component dispersion that is formed and frozen. Water isremoved from the frozen matrix by either lyophilization or submersion inalcohol (solvent extraction) to produce a dry unit. The product formedhas uniform porosity and adequate strength for handling, with propertiessimilar to those previously described.

LYOC™ starts with an oil-in-water emulsion and is placed directly intoblister cavities followed by freeze drying. To maintain homogeneityduring freezing, polymers must be included to increase the matrixviscosity to an almost paste-like consistency to prevent sedimentation.The increased matrix viscosity reduces the product porosity, therebyincreasing freeze drying times and having a negative impact ondisintegration.

If not specified herein, percentages refer to weight/volume.

In one embodiment, a relatively low immediate release is the initialdose, followed by administration of an extended release formulation. Inone embodiment 10 mg is the low immediate release dose followed by 20mg-30 mg extended release over 24 h.

Unless otherwise indicated, a formulation is a dosage form. A tablet isa non-limiting example of a dosage form. Dispersion and disintegrationof the formulation are used synonymously. As used herein, the activeagent, abbreviated “active”, includes domperidone, derivatives ofdomperidone, analogs of domperidone, deuterated domperidone, etc.

The active includes all forms of the domperidone active, includingdeuterated forms of domperidone, and also includes but is not limited tointermediates, metabolites, enantiomers, polymorphs, crystallinestructure, hydrates, stereoisomers, salts, bases, complexes, carriers,analogs, derivatives, and conjugates As used herein, extended releaseand sustained release are generally used synonymously.

Each of a bead and a pellet is any discrete component of a dosage form,e.g., a capsule shell may be filled with a plurality of beads and/or aplurality of pellets.

Modified release (MR) dosage forms include, but are not limited to, thefollowing:

An immediate release formulation and a delayed release formulationindicate the onset of release of the active in relationship toadministration. An immediate release formulation indicates release ofthe active from the formulation beginning within a relatively shorterperiod of time post administration, e.g. a few minutes or less. Adelayed release formulation indicates release of the active from theformulation does not begin within a relatively shorter period of timeafter administration, but instead is delayed and begins or is triggeredafter a relatively longer period of time post administration, e.g., morethan one hour.

A rapid release formulation and a slow release formulation indicate therate of release after onset. Once delivery of the active begins, theactive may be released relatively rapidly or relatively slowly. A rapidrelease indicates that, after onset, a maximum or peak dose is reachedin a relatively shorter period of time. A slow release indicates that,after onset, a maximum or peak dose is reached in a relatively longerperiod of time. Once reached, the maximum dose may fall off at any rate,e.g. fast, slow, or constant.

A sustained release formulation and a continuous release formulationindicate the period of on-going release, and means that the delivery ofactive continues or is sustained for an extended period of time afterinitial onset, typically more than one hour, whatever the shape of thedose release profile. For example, the release of active is sustainedbetween a maximum and minimum value of more than zero for somerelatively longer period of time. This release may be at a constantdose, or at a dose that diminishes over time.

A constant release formulation indicates the dose that is beingreleased. A constant release means that an active is delivered at arelatively constant dose over a moderate or extended period of time.This can be represented by a dose release profile that is relativelyflat or only gently sloped after initial onset, i.e. without highlydistinct peaks and valleys. Thus, a constant release is typicallysustained or continuous, but a sustained or continuous release may notbe constant.

A pulsed release formulation indicates that an active is delivered inone or more doses that fluctuate between a maximum dose and a minimumdose over a period of time. This can be represented by a dose releaseprofile having one or more distinct peaks or valleys. However, two ormore pulsed releases may produce an overlapping, overall, or compositerelease profile that appears to be or effectively is constant. When twoor more pulsed releases occur, there may or may not be a period of norelease between pulses. Typically, pulsed release results in release ofessentially all of an active within about 60 minutes or less.

An extended release formulation provides either a release of activewithin a targeted dose range for a relatively longer period, or a plasmalevel of drug within a targeted dose range for a relatively longerperiod, without regard for the particular mechanism or character ofrelease, e.g. as sustained, pulsed, or constant.

A release profile for an orally administered drug indicates the mannerand timing by which a formulation releases or delivers the active to thestomach, intestines, etc. upon administration. Various methods are knownto evaluate drug release and produce release profiles, including invitro tests that model in vivo behavior of a formulation and thatinclude USP dissolution testing for immediate release and controlledrelease solid dosage forms.

Drug release profiles are distinct from plasma profiles. A plasmaprofile indicates the dose or level of active in the bloodstream of amammal, e.g. a patient receiving a drug formulation. When an active isreleased from a formulation, e.g. into the gut, the amount of activepresent in the bloodstream over time can be determined.

A drug release profile may be designed to produce a desired or targetedplasma profile, and a plasma profile may mimic a release profile. Forexample, while a sustained release of active would be expected toproduce a sustained dose in the plasma, and a pulsed release would beexpected to produce a pulsed (peak and valley) plasma profile, this isnot necessarily the case. The half-life (t_(1/2)) of the active in theblood stream (its rate of decay) may be such that a sustained orcontinuous plasma profile could result from a pulsed delivery profile.Other factors may also play a role, such as bioabsorption,bioavailability, and first pass effect. The plasma profile produced by aparticular active release profile may also vary from patient to patient.

Measures of bioavailability are known in the art and include the areaunder the plasma concentration-time curve (AUC), the concentrationmaximum (C_(max)), and the time to C_(max) (T_(max)).

AUC measures the area under a plasma concentration-time curve, andrepresents the amount of drug absorbed following administration of asingle dose of a drug (Remington: The Science and Practice of Pharmacy,Editor Gennaro 2000, p. 999).

C_(max) is the maximum plasma concentration achieved after oral drugadministration (Remington, page 999). An oral drug administrationresults in one C_(max), but may result in more than one peak plasmaconcentration, e.g., following administration of a pulsed doseformulation.

T_(max) is the amount of time necessary to achieve the C_(max) afteroral drug administration, and is related to the rate of absorption ofthe active (Remington p. 999).

A “solubility-enhancing polymer” or “crystallization-inhibiting polymer”refer to a water-soluble polymer capable, at suitable concentrations, offorming a solid dispersion, as defined herein, of a weakly basicmeclizine in the solubility-enhancing polymer, e.g., by first dissolvingboth the drug and polymer in the same solvent system, and then removingthe solvent under appropriate conditions. The weakly basic drug ismaintained substantially as a molecular dispersion or in amorphous formduring storage, transportation, and commercial distribution of thecomposition containing the solid dispersion of the solubility-enhancingpolymer and weakly basic drug.

A “controlled-release” coating encompasses coatings that delay release,sustain release, prevent release, and/or otherwise prolong the releaseof a drug from a particle coated with a controlled-release coating. Theterm “controlled-release” encompasses “sustained-release,” “delayedrelease” and “timed, pulsatile release”, thus a “controlled-releasecoating” encompasses a sustained release coating, timed, pulsatilerelease coating or “lag-time” coating.

An “enteric polymer” refers to a pH sensitive polymer that is resistantto gastric juice (i.e., relatively insoluble at the low pH levels foundin the stomach), and which dissolves at the higher pH levels found inthe intestinal tract.

“Immediate release”, in reference to a pharmaceutical composition thatcan be a dosage form or a component of a dosage form, refers to apharmaceutical composition that releases greater than or equal to about50% of the active, in another embodiment greater than about 75% of theactive, in another embodiment greater than about 90% of the active, andin other embodiments greater than about 95% of the active within aboutone hour following administration of the dosage form. The term can alsorefer to pharmaceutical compositions in which the relatively rapidrelease of active occurs after a lag time in which little or no releaseof active occurs.

An “immediate release (IR) bead” or “immediate release particle” broadlyrefers to a bead or particle containing active that exhibits “immediaterelease” properties with respect to the active.

A “sustained release (SR) bead” or “sustained release particle” broadlyrefers to a bead or particle containing a SR coating disposed over anactive-containing core.

A “lag-time coating” or “timed, pulsatile release coating” (TRP) refersto a controlled-release coating combining water-insoluble and entericpolymers; a TPR coating by itself provides an immediate release pulse ofthe active after a predetermined lag-time. A timed, sustained release(TSR) bead with a TPR coating disposed over a barrier coating (SRcoating) provides a sustained active-release profile after apredetermined lag time.

A “delayed release (DR) bead” or “delayed release particle” broadlyrefers to an active-containing core. A DR coating refers to acontrolled-release coating comprising an enteric polymer, optionally incombination with a plasticizer.

A “controlled release (CR) bead” or “controlled release particle”broadly refers to an active-containing core having an inner SR coatingoptionally followed by an outer DR or TPR coating or an inner TPRcoating followed by an outer DR coating.

“Lag-time” refers to a time period where less than about 10% of theactive is released from a pharmaceutical composition after ingestion ofthe composition or a dosage form comprising the composition, or afterexposure of the composition or dosage form comprising the composition,to simulated body fluid(s), e.g., evaluated with a USP apparatus using atwo-stage dissolution medium (first 2 hours in 700 mL of 0.1N HCl at 37°C. followed by dissolution testing at pH 6.8 obtained by the addition of200 mL of a pH modifier).

“Disposed over”, e.g. in reference to a coating over a substrate, refersto the relative location of e.g. the coating in reference to thesubstrate, but does not require that the coating be in direct contactwith the substrate. For example, a first coating “disposed over” asubstrate can be in direct contact with the substrate, or one or moreintervening materials or coatings can be interposed between the firstcoating and the substrate. For example, a SR coating disposed over anactive-containing core can refer to a SR coating deposited directly overthe active-containing core or acid crystal or acid-containing core, orcan refer to a SR coating deposited onto a protective seal coatingdeposited on the active-containing core.

A “sealant layer” or “protective seal coating” refers to a protectivemembrane disposed over an active-containing core particle or afunctional polymer coating, protecting the particle from abrasion andattrition during handling, and/or minimizing static during processing.

An “orally disintegrating tablet” or “ODT” refers to a tablet thatdisintegrates rapidly in the oral cavity after administration withoutchewing. The disintegration rate can vary, but is faster than thedisintegration rate of conventional solid dosage forms (e.g., tablets orcapsules) that are intended to be swallowed immediately afteradministration, or faster than the disintegration rate of chewable soliddosage forms, when tested e.g. the USP <701> test method

The term “substantially disintegrates” refers to a level ofdisintegration amounting to disintegration of at least about 50%, atleast about 60%, at least about 70%, at least about 80%, at least about90%, or about 100% disintegration. “Disintegration” is distinguishedfrom “dissolution”; “disintegration” refers to the breaking up of orloss of structural cohesion of, e.g., the constituent particlescomprising a tablet, whereas “dissolution” refers to the solubilizationof a solid in a liquid, e.g., the solubilization of a drug in solventsor gastric fluids.

A “water-insoluble polymer” is a polymer that is insoluble or verysparingly soluble in aqueous media, independent of pH, or over a broadpH range (e.g., pH 0 to pH 14). A polymer that swells but does notdissolve in aqueous media can be “water-insoluble”.

A “water-soluble polymer” is a polymer that is soluble, i.e., asignificant amount dissolves, in aqueous media, independent of pH.

An “enteric polymer” is a polymer that is soluble, i.e., a significantamount dissolves, under intestinal conditions; i.e., in aqueous mediaunder neutral to alkaline conditions and insoluble under acidicconditions (i.e., low pH).

A “reverse enteric polymer” or “gastro-soluble polymer” refers to apolymer that is soluble under acidic conditions and insoluble underneutral and alkaline conditions.

Unless stated otherwise, the amount of the various coatings or layersdescribed herein (the “coating weight”) is expressed as the percentageweight gain of the particles or beads provided by the dried coating,relative to the initial weight of the particles or beads prior tocoating. Thus, a 10% coating weight refers to a dried coating whichincreases the weight of a particle by 10%.

Bioequivalence is the absence of a significantly different rate andextent of absorption in the availability of the active ingredient whenadministered at the same dose under similar conditions. Bioequivalencecan be measured by pharmacokinetic parameters, e.g., AUC and C_(max).

One embodiment is an oral formulation that contains a modified releaseformulation (MR). In this embodiment, a single dosage form contains bothan immediate release (IR) dosage form and an extended release (XR)dosage form. As used herein, an immediate release dosage form releasesactive immediately upon administration. As used herein, an extendedrelease dosage form encompasses delayed release, time release,controlled release, or sustained release forms. As used herein, anextended release dosage form releases active at a predetermined rateover time in order to maintain a constant drug concentration for aspecific period of time with minimum side effects. Extended releaseformulations may be achieved by a variety of formulations assubsequently described with illustrative but not limiting examples,including polymer conjugates with the active and liposome formulationsof the active.

The delivery system may comprise a core, seed, or matrix that may or maynot be loaded with active, and one or more coating layers comprisingactive and/or comprising a layer having release characteristics thatcontrols the onset and release characteristics of the active. The core,seed, or matrix may be prepared or obtained commercially. As only oneexample, there may be a sugar or microcrystalline cellulose core, with ahydrophilic matrix made from, e.g., hydroxypropyl methylcellulose(HPMC), hydroxypropyl cellulose (HPC), poly(ethylene oxide), poly(vinylalcohol), xanthan gum, carbomer, carrageenan, zooglan, etc.

Coating layers can provide immediate release, delayed pulsed release, orsustained release. Immediate release of the active from theimmediate-release layer can be by, e.g., using a very thin layer orcoating that gastric fluids can quickly penetrate, facilitating rapidleaching of the active; or incorporating the active in a mixture thatincludes a supporting binder or other inert material that readilydissolves and release active in gastric fluid; or using a supportingbinder or other inert material that rapidly disintegrates upon contactwith gastric fluid, with both the material and the active quicklydispersing into gastric fluid as small particles. Such rapidlydisintegrating and dispersing materials include, e.g., lactose andmicrocrystalline cellulose. Hydroxypropyl methylcellulose is an exampleof a suspending agent and binder.

Enteric coatings for the delayed pulsed release component can bepH-dependent or pH-independent. Enteric coatings for the sustainedrelease component are pH dependent. A pH dependent coating is activatedto release drug within a known pH range, which typically is matched tothe local pH of the environment where delayed release is desired.Exemplary pH dependent coatings include cellulose acetate phthalate,cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate,polyvinyl acetate phthalate, carboxymethylethylcellulose, co-polymerizedmethacrylic acid/methacrylic acid methyl esters such as, e.g., materialsknown under the trade name EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5,S100 or similar compounds used to obtain enteric coatings. Aqueouscolloidal polymer dispersions or re-dispersions can be also applied,e.g. EUDRAGIT® L 30D-55, EUDRAGIT® L100-55, EUDRAGIT® 5100, EUDRAGIT®preparation 4110D (Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC);KOLLICOAT MAE® 30D and. 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

Examples of commercially available pharmaceutical formulations using anenteric system in the form of a coating or layer to prevent the activefrom dissolving in the stomach include CYMBALTA® (duloxetine HCl, LillyIndianapolis Ind.), NEXIUM® (esomeprazole, AstraZeneca LP), ACIPHEX®(rabeprazole sodium, Eisai Inc. and Ortho-Mc-Neil-JanssenPharmaceuticals, Inc.), ASACOL® HD (me-salamine, Procter & GamblePharmaceuticals, Inc.), LIALDA® (mesalamine, Shire US), PENTASA®(me-salamine, Shire US), ENTECORT® EC (budesonide capsules,AstraZeneca), LAMICTAL® XR (lamotrigine tablets, GlaxoSmithKline),KAPIDEX® (dexlansoprazole, Takeda Pharmaceuticals North America, Inc.),CREON® (pan-creatin capsules, Solvay S.A), ULTRASE® (pancrelipasecapsules, Axcan Pharma US), PROTONIX® (pantoprazole, Pfizer) DEPAKOTE®(divalproex sodium, Abbott Laboratories), PRILOSEC® (omeprazole,AstraZeneca), PREVACID® (lanzoprazole, Novartis Consumer Health),ARTHOTEC® (diclofenac sodium, Pfizer); STAVZOR® (valproic acid, NovenTherapeutics), TRILIPIXI 4 (fenofibric acid delayed release capsules,Abbott Laboratories), and VIDEX® EC (didanosine, Bristol-Myers Squibb).

An alcohol-resistant pharmaceutical composition uses an “alcoholprotectant” to prevent or retard ethanol-induced “dumping” of the activeagent from the dosage form that could cause too high of a dose ofdomperidone or deuterated domperidone to be released into the patient,which could then produce a higher C_(max), potentially causing QTprolongation. With an alcohol-resistant composition, dose dumping isavoided, alleviating this safety concern. The alcohol protectant may bea single material, e.g. a polymer, or a combination of materials, e.g.,combination of polymers, in an excipient solution. The alcoholprotectant is deposited in a layer or coating, or it is in the form of amatrix in alternative embodiments. Alcohol protectant materials include,but are not limited to, organic based cellulose acetate phthalate,ammonium methacrylate copolymers, methacrylate ester copolymers,methacrylic acid copolymers, natural and synthetic starches,polyalkylene oxides, and natural and synthetic celluloses includingmodified celluloses such as hydroxypropylmethylcellulose (HPMC),hydroxypropylcellulose (HPC) hydroxymethylcellulose (HMC),methylcellulose (MC), hydroxyethylcellulose (HEC), andcarboxymethylcellulose (CMC), waxes such as insect and animal waxes,vegetable waxes, mineral waxes, petroleum waxes, and synthetic waxes. Inone embodiment, the alcohol protectant is an organic based celluloseacetate phthalate Eastman C-A-P® or Cellacefate, NF (Eastman ChemicalCompany, Kingsport Tenn. USA). The alcohol protectant may be present inthe formulation in an amount sufficient to impart alcohol resistance ata given ethanol concentration, e.g., added in an amount of 20%, 25%,30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%100%, 150%, 200%, 250%, 300%, 350%, 400%, 450% and 500% by weight gain.

In one embodiment, the active composition comprises a plurality of CRand IR particles, where the CR particles each comprises a core coatedwith a water-insoluble polymer layer, followed by a coating layercomprising an enteric polymer optionally in combination with awater-insoluble polymer, where the core comprises domperidone and apharmaceutically acceptable polymeric binder, followed by a firstcoating layer comprising a water-insoluble polymer optionally incombination with a water-soluble polymer and an optional second coatingof an enteric polymer optionally in combination with a water-insolublepolymer.

One embodiment has a plurality of CR and IR particles. The CR particlecomprises a core coated with a water-insoluble polymer layer, followedby a coating layer comprising an enteric polymer optionally incombination with a water-insoluble polymer; the core comprising theactive and a pharmaceutically acceptable organic acid (e.g. fumaricacid) separated from each other at least by a SR layer. The IR particleseach comprise the active in combination with suitable excipients. Incertain embodiments, the composition comprises the active and at leastone solubility-enhancing organic acid that is capable of creating anacidic pH microenvironment within the coated bead to solubilize theactive prior to its release into a hostile pH environment of theintestinal tract where the drug is practically insoluble.

In one embodiment, the CR particles comprise an inert core (e.g., asugar sphere, cellulosic sphere, etc.) sequentially coated with apharmaceutically acceptable organic acid (e.g., succinic acid) and apharmaceutically acceptable binder (e.g., hydroxypropyl cellulose); a SRlayer (e.g., comprising a pharmaceutically acceptable water insolublepolymer such as ethyl cellulose, optionally plasticized with apharmaceutically acceptable plasticizer such as triethyl citrate orpolyethylene glycol); a active layer, and a pharmaceutically acceptablebinder (e.g., povidone); an optional sealing layer (e.g. comprising awater soluble polymer such as hydroxypropyl methyl cellulose); and a SRlayer comprising a water insoluble polymer such as ethyl cellulose(EC-10), and an enteric polymer such as hypromellose phthalate, HP-55,and an optional pharmaceutically acceptable plasticizer such as triethylcitrate (TEC).

A pH independent coating includes materials susceptible to enzymaticactivation by azo-reductases in intestinal bacteria (i.e., azo-polymers)or materials susceptible to degradation by polysaccaridases in the colon(natural polysaccarides). Non-limiting examples of azo-polymers includeco-polymers of 2-hydroxyethyl methacrylate (HEMA) and methylmethacrylate (MMA). Non-limiting examples of natural polysaccharidesinclude amylose, chitosan, chrondoitin, dextran, and xylan.

An “enteric polymer” is a polymer having a polystyrene equivalent weightaverage molecular weight (MW) of about 50,000 to 150,000, and containingcarboxyl groups that remain insoluble at a pH below about pH 4 (gastricpH range), but that ionize, and thus cause the polymer to dissolve, at apH above about 5.0 (intestinal pH range). The enteric polymer may befilm-forming, e.g., cellulose acetate phthalate (C-A-P), celluloseacetate trimellitate (C-A-T), hydroxypropylmethylcellulose phthalate(HPMCP), copolymer of methacrylic acid and ethyl acrylate,hydroxypropylmethyl-cellulose acetate succinate (HPMCAS), and polyvinylacetate phthalate (PVAP). The MW of HPMCP may be between about 80,000and 110,000, or between 95,000 and 100,000. The MW for C-A-P may bebetween about 55,000 and 75,000, or between 68,000 and 80,000.

The sustained release component can include sustained release coatings,sustained release matrices, and sustained release osmotic systems.Sustained release coatings can be prepared using a water-insolublepolymer, a combination of water-insoluble polymers, or a combinationwater-insoluble and water-soluble polymers. Conventional sustainedrelease polymers are known to those of ordinary skill in the art can beused for the sustained release matrix.

Exemplary sustained release coatings include polyvinyl acetate,cellulose acetate, cellulose acetate butyrate, cellulose acetatepropionate, ethyl cellulose, fatty acids and esters thereof, alkylalcohols, waxes, zein (prolamine from corn), and aqueous polymericdispersions such as EUDRAGIT® RS and RL30D, EUDRAGIT® NE30D, AQUACOAT®,SURELEASE®, KOLLICOAT® SR30D, and cellulose acetate latex.

Pellets or beads can be made of any pharmaceutically acceptablematerials, based on compatibility with the active and thephysicochemical properties of the pellets or beads.

Binders include cellulose derivatives such as methylcellulose,hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone, polyvinylpyrrolidone/vinylacetate copolymer, etc.

Disintegration agents include corn starch, pregelatinized starch,cross-linked carboxymethylcellulose (AC-DI-SOL®), sodium starchglycolate (EXPLOTAB®), cross-linked polyvinylpyrrolidone (PLASDONE XL®),etc.

Filling agents include lactose, calcium carbonate, calcium phosphate,calcium sulfate, microcrystalline cellulose, dextran, starches, sucrose,xylitol, lactitol, mannitol, sorbitol, sodium chloride, polyethyleneglycol, etc.

Surfactants include sodium lauryl sulfate, sorbitan monooleate,polyoxyethylene sorbitan monooleate, bile salts, glyceryl monostearate,PLURONIC® line (BASF), etc.

Solubilizers include citric acid, succinic acid, fumaric acid, malicacid, tartaric acid, maleic acid, glutaric acid, sodium bicarbonate,sodium carbonate, etc.

Stabilizers include antioxidation agents, buffers, acids, etc.

The following information illustrates exemplary but non-limitingmanufacturing methods.

The core may be prepared by extrusion-spheronization, high-sheargranulation, solution or suspension layering,

In extrusion-spheronization, the active and other additives aregranulated by adding a binder solution. The wet mass is passed throughan extruder equipped with a certain size screen. The extrudates arespheronized in a marumerizer. The resulting pellets are dried andsieved.

In high-shear granulation, the active and other additives are dry-mixed,then the mixture is wetted by adding a binder solution in a highshear-granulator/mixer. The granules are kneaded after wetting by thecombined actions of mixing and milling. The resulting granules orpellets are dried and sieved.

In solution or suspension layering, a drug solution or dispersion withor without a binder is sprayed onto starting seeds with a certainparticle size in a fluid bed processor or other suitable equipment, thuscoating the active on the surface of the starting seeds. Theactive-loaded pellets are dried.

Core particles have a diameter ranging from about 50 microns-1500microns, preferably 100 microns-800 microns. Core particles may becoated in a fluidized bed apparatus with an alternating sequence ofcoating layers. The core may be coated directly with a layer or layersof the active, and/or the active may be incorporated into the corematerial. A separation or protective layer may be added on top of theactive containing layer, and/or between active layers. A separation orprotective layer may be added onto the surface of the active-loadedcore, and then the enteric delayed pulsed or sustained release layer maybe coated thereupon. Another active layer may also be added to theenteric delayed pulsed or sustained layer to deliver an initial dose. Aprotective coating layer may be applied immediately outside either anactive-containing core or an active-layered core, by conventionalcoating techniques used in the art, such as pan coating or fluid bedcoating, using solutions of polymers in water or suitable organicsolvents, or aqueous polymer dispersions. Suitable materials for theprotective layer include cellulose derivatives such as hydroxyethylcellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,polyvinylpyrrolidone, polyvinylpyrrolidone/vinyl acetate copolymer,ethyl cellulose aqueous dispersions (AQUACOAT®, SURELEASE®), EUDRAGIT®RL 30D, OPADRY®, cellulose acetate, cellulose acetate butyrate,cellulose acetate propionate, ethyl cellulose, fatty acids and theiresters, waxes, zein, and aqueous polymer dispersions such as EUDRAGIT®RS and RL 30D, EUDRAGIT® NE 30D, AQUACOAT®, SURELEASE®, and/or celluloseacetate latex, alone or combined with hydrophilic polymers such ashydroxyethyl cellulose, hydroxypropyl cellulose (KLUCEL®, HerculesCorp.), hydroxypropyl methylcellulose (METHOCEL®, Dow Chemical Corp.),polyvinylpyrrolidone, etc. Coating levels range from about 1% w/w toabout 6% w/w, preferably about 2% w/w to about 4% w/w.

The enteric delayed pulsed release or sustained release coating layer isapplied to the core, with or without seal coating, by conventionalcoating techniques known in the art, e.g., pan coating or fluid bedcoating, using solutions of polymers in water or suitable organicsolvents, or using aqueous polymer dispersions. Suitable coaters areknown in the art, e.g., commercially available pH-sensitive polymers sothat the active is not released in the acidic stomach environment(pH<4.5), but is released and become available when the pH-sensitivelayer dissolves at a higher pH, after a certain delayed time, or afterthe unit passes through the stomach.

Enteric polymers for the delayed pulsed release component and sustainedrelease component include, e.g., cellulose acetate phthalate, celluloseacetate trimellitate, hydroxypropyl methylcellulose phthalate, polyvinylacetate phthalate, carboxymethylethylcellulose, co-polymerizedmethacrylic acid/methacrylic acid methyl esters such as, e.g., materialsknown as EUDRAGIT® L12.5, L100, or EUDRAGIT® S12.5, S100 or similarcompounds used to obtain enteric coatings. Aqueous colloidal polymerdispersions or re-dispersions can be also applied, e.g. EUDRAGIT® L30D-55, EUDRAGIT® L100-55, EUDRAGIT® 5100, EUDRAGIT® preparation 4110D(Rohm Pharma); AQUATERIC®, AQUACOAT® CPD 30 (FMC); KOLLICOAT MAE® 30Dand. 30DP (BASF); EASTACRYL® 30D (Eastman Chemical).

The enteric delayed pulsed release and sustained release polymers can bemodified by mixing with other known coating products that are not pHsensitive, e.g., neutral methacrylic acid esters with a small portion oftrimethylammonioethyl methacrylate chloride commercially available asEUDRAGIT® RS and EUDRAGIT® RL; a neutral ester dispersion without anyfunctional groups commercially available as EUDRAGIT® NE30D; and otherpH independent coating products.

The modifying component of the protective layer used over the entericdelayed pulsed release or sustained release coating can include a waterpenetration barrier layer (semipermeable polymer) that can besuccessively coated after the enteric coating to reduce the waterpenetration rate through the enteric coating layer and thus increase thelag time of the active release. Coating is performed as previouslydescribed.

An protective or colorant overcoating layer can optionally be applied.OPADRY®, OPADRY II® (COLORCON®) and corresponding color and colorlessgrades from COLORCON® can protect the pellets from being tacky andprovide colors to the product. In one embodiment the protectant or colorcoating ranges from 1% w/w to 6% w/w, preferably about 2% w/w to about3% w/w. Talc can also be used.

Components may be incorporated into the overcoating formula, e.g., tofacilitate and provide even more rapid release. Such components include,e.g., plasticizers including acetyltriethyl citrate, triethyl citrate,acetyltributyl citrate, dibutylsebacate, triacetin, polyethyleneglycols, propylene glycol, etc.; lubricants including talc, colloidalsilica dioxide, magnesium stearate, calcium stearate, titanium dioxide,magnesium silicate, etc.

The composition may be incorporated into hard gelatin capsules, eitheralone or with additional excipients. The composition may be incorporatedinto a tablet, e.g., by incorporation into a tablet matrix that rapidlydisperses the particles after ingestion. To prevent particle destructionduring the tableting process, a filler/binder is required, e.g.,microcrystalline cellulose (AVICEL®), soy polysaccharide (EMCOSOY®),pre-gelatinized starches (STARCH® 1500, NATIONAL® 1551), andpolyethylene glycols (CARBOWAX®), present in the range of about 5% w/wto about 75% w/w, with a preferred range of about 25% w/w to about 50%w/w.

Excipients typically include, but are not limited to, one or more inertfillers including microcrystalline cellulose, soy polysaccharides,calcium phosphate dihydrate, calcium sulfate, lactose, sucrose,sorbitol, etc.; one or more materials that impart flow to powdersincluding fumed silicon dioxide, silica gel, magnesium stearate, calciumstearate, etc.; one or more lubricants to insure proper tabletingincluding polyethylene glycol, leucine, glyceryl behenate, magnesiumstearate, calcium stearate, stearic acid, hydrogenated vegetable oil,etc. present in the range of about 0.1% w/w to about 10% w/w, with apreferred range of about 0.3% w/w to about 3.0% w/w.

Disintegrants are added to disperse the beads once the tablet isingested. Disintegrants include, but are not limited to, cross-linkedsodium carboxymethyl cellulose (AC-DI-SOL®), sodium starch glycolate(EXPLOTAB®, PRIMOJEL®), cross-linked polyvinylpolypyrrolidone(PLASDONE-XL®), etc., present in the range of about 3% w/w to about 15%w/w, with a preferred range of about 5% w/w to about 10% w/w.

In one embodiment, tablets are formed from particles that are introducedinto a blender with AVICEL®, disintegrants, and lubricant, mixed for adefined time (minutes) to achieve a homogeneous blend, then the blend isplaced in the hopper of a tablet press with which tablets arecompressed. The compression force used is adequate to form a tablet butnot to fracture the beads or coatings.

A tablet can be constructed in three layers, where the immediate releasecomponent is dry blended, and the delayed pulsed release and thesustained release components are wet granulated. The tablet is thenformed in a one layer or a three layer compression. Upon dissolution oflayers, each component is released and acts as formulated: e.g., theimmediate release particles provide immediate release, the delayedpulsed release particles provide delayed pulsed release, and thesustained release particles provide sustained release after a lag time.

One embodiment of the invention is an oral domperidone or deuterateddomperidone formulation that contains, in a single dosage form, both animmediate release form and an extended release form. One embodiment ofthe invention is an oral domperidone or deuterated domperidoneformulation that contains, in a single dosage form, both an immediaterelease form and an extended release form.

A dosage form of domperidone or deuterated domperidone that combinesboth an immediate release formulation of 10 mg, ranging from 5 mg to 20mg, and an extended release formulation of 20 mg, ranging from 10 mg to80 mg, provides agent delivery to the patient continuously over about a12 hr period. Such a dosage formulation provides therapy over 12 hrswith a single patient dosage, providing patient convenience and extendedtherapy, e.g., a patient may beneficially experience a complete night ofsleep, a complete work day, a complete leisure day, etc. withoutsymptoms.

In embodiments, the inventive formulation contains an immediate release(IR) portion or component of the composition, and an extended release(XR) portion or component, or combinations thereof. The immediaterelease portion delivers 100% of the immediate release dose in less thanabout hour, and the extended release portion delivers the extendedrelease dose over a period of 12 hours.

A typical dissolution profile, also termed a release profile, ofdomperidone is shown in FIG. 2. The percent of drug release approaches100% in less than or within one hour in the immediate release portion ofthe delivery system, and about 100% within or less than 12 hours for theextended release portion of the delivery system. FIG. 3 is a schematicof a simulated plasma concentration of domperidone, where the plasmadrug concentration from the immediate release portion peaks at abouttwice the concentration at the same time the drug from the extendedrelease portion reaches a plateau, about half of that from the immediaterelease portion.

In one embodiment, the active may be administered rectally. Rectaladministration of the active may be 10 mg-20 mg three times daily.Rectal administration may be by a suppository formulation. In oneembodiment, the formulation is administered rectally, e.g., bysuppository.

The composition may take a variety of delivery forms or systems. Thefollowing formulations may be used, these are exemplary only andnon-limiting. Oral formulations include a tablet, capsule, sachet, softgel, liquid, gel, strip, film, powder, granule, gel, pulsatile release,coated core, delayed extended release form, banded drug form, sustainedrelease form, tablet capsule, granulation caplet, layered tablet, etc.,including combinations of these, e.g., a tablet capsule, a granulationcaplet, a layered tablet, etc. with active and at least onepharmaceutically acceptable excipient.

A tablet formulation is known to one skilled in the art. The tablet maybe of any shape or size convenient for oral administration, e.g.,circular, elliptical, etc. In one embodiment, the tablet may be eitherfor immediate release (IR), extended release (XR), or combinationsthereof. The tablet may be a bilayer tablet containing IR and XR layersadjacent to each other (FIG. 4); a trilayer tablet containing both IRand XR layers separated by a pharmaceutically acceptable buffer layer(FIG. 5); or a XR tablet containing the active in the matrix layer andcoated with an IR layer of active (FIG. 6).

The composition may also be provided in other delivery forms, e.g., acapsule containing an IR tablet, a plug, and a XR tablet within anosmotic drug delivery system for controlled delivery of the compositionover a duration of 12 hours (FIG. 7); a capsule containing IR beads andXR beads mixed in the appropriate ratios (FIG. 8); a capsule containingIR mini-tablets mixed with XR mini-tablets (FIG. 9); a capsulecontaining IR granules and XR granules that are coated with extendedrelease polymers (FIG. 10); a capsule containing XR beads that arecoated with a IR layer (FIG. 11), etc. Other delivery forms of theactive may be a compressed tablet containing IR granules and coated XRbeads that are embedded within the tablet (FIG. 12); a compressed tabletcontaining a XR tablet embedded within the IR tablet (FIG. 13); or a XRtablet suspended in an immediate release liquid drug solution within acapsule (FIG. 14).

Another delivery form is a sachet. A sachet may contain a mixture of IRand XR granules or beads (FIG. 15), or it may contain a mixture ofeffervescent IR granules and coated XR granules (FIG. 16).

Other immediate, extended, or sustained, modified, and delayed pulserelease systems are described in each of the following references U.S.Publication Nos. 2005/0095295, 2005/0106247, and 2007/0264323; and U.S.Pat. Nos. 6,126,969 and 8,211,465. As one example, U.S. Publication No.2005/0106247 describes a drug (cyclobenzaprine hydrochloride) inextended release particles such as beads, pellets, granules, etc. havingan extended release coating comprising a water insoluble polymer, and/orwater soluble polymer, and some of the particles are contained in agelatin capsule. As another example, U.S. Publication No. 2007/0264323describes delivery systems for a drug (ADDERALL®) such as beads withincapsules, tablets, or sachets including coating layers, delayed pulsedrelease components, immediate release formulations, intermediate releaseformulations, sustained release formulations, and controlled releasecapsules. U.S. Pat. No. 6,126,969 describes delivery systems for a drug(acetaminophen) such as a combination of coated and uncoated drugparticles for an immediate-release/sustained release dosage form. U.S.Pat. No. 8,211,465 describes dosage forms for an initial release of adrug (NSAID such as ibuprofen) and a second sustained release of thesame drug. An osmotic delivery system is described in Patra et al.Osmotic Drug Delivery Systems: Basis and Design Approaches, RecentPatents on Drug Delivery and Formulation, 7 (2013) 1-12.

The active core of the dosage form may be an inert particle or an acidicor alkaline buffer crystal, which is coated with a drug-containingfilm-forming formulation. In one embodiment a water-soluble film formingcomposition forms a water-soluble/dispersible particle. Alternatively,the active may be prepared by granulating and milling and/or byextrusion and spheronization of a polymer composition containing theactive. The amount of active in the core depends on the dose that isrequired, and typically varies from about 5 weight % to 60 weight %. Thepolymeric coating on the active core will typically be from about 4% to20% based on the weight of the coated particle, depending on the type ofrelease profile required and/or the selected polymers and coatingsolvents. Those skilled in the art will be able to select an appropriateamount of active for coating onto or incorporating into the core toachieve the desired dosage. In one embodiment, the inactive core may bea sugar sphere or a buffer crystal or an encapsulated buffer crystalsuch as calcium carbonate, sodium bicarbonate, fumaric acid, tartaricacid, etc. which alters the microenvironment of the active to facilitateits release.

The drug-containing particle may be coated with an extended release (XR)coating comprising a water insoluble polymer or a combination of a waterinsoluble polymer and a water soluble polymer to provide XR beads. Inembodiments, the water insoluble polymer and the water soluble polymermay be present at a weight ratio of from 100:0 to 65:35, or from about95:5 to 70:30, or from about 85:15 to 75:25. The extended releasecoating is applied in an amount necessary to provide the desired releaseprofile. In embodiments, the extended release coating is from about 1%to 15% by weight of the coated beads, or from about 7% to 12% by weightof the coated beads.

The modified release dosage form, including a mixture of two beadpopulations, may be made as follows. A drug-containing core is preparedby coating an inert particle, such as a non-pareil seed, an acidicbuffer crystal or an alkaline buffer crystal with an active and apolymeric binder or by granulation and milling or byextrusion/spheronization to form an IR bead. The IR bead is coated witha plasticized water-insoluble polymer alone such as ethylcellulose or incombination with a water soluble polymer such ashydroxypropylmethylcellulose to form an XR bead. Hard gelatin capsulesXR beads, alone or combined with IR beads, are filled at a desired ratioto produce modified release (MR) capsules providing the desired releaseprofile.

IR beads using the following dissolution procedure have been reported torelease at least about 70%, more specifically at least about 90%, of theactive within 30 minutes.

A USP Apparatus 2 (paddles at 50 rpm) is used with the followingdissolution medium: 900 mL 0.1 N HCl (or suitable dissolution medium) at37° C., with active release determined by HPLC.

An aqueous or a pharmaceutically acceptable solvent may be used forpreparing active-containing core particles. The type of film formingbinder that is used to bind the drug to the inert sugar sphere is notcritical but usually water soluble, alcohol soluble, or acetone/watersoluble binders are used. Binders such as polyvinylpyrrolidone (PVP),polyethylene oxide, hydroxypropyl methylcellulose (HPMC),hydroxypropylcellulose (HPC), polysaccharides such as dextran, cornstarch may be used at concentrations from about 0.5 weight % to about 5weight %, with other concentrations also being used. The active may bepresent in this coating formulation in the solution form or may bedispersed at a solid content up to about 35 weight % depending on theviscosity of the coating formulation.

The active, optionally a binder such as PVP, a dissolution ratecontrolling polymer if used, and optionally other pharmaceuticallyacceptable excipients are blended in a planetary mixer or a high sheargranulator such as FIELDER® and granulated by adding/spraying agranulating fluid such as water or alcohol. The wet mass can be extrudedand spheronized to produce spherical particles (beads) using anextruder/marumerizer. In these embodiments, the active load may be ashigh as 90% by weight based on the total weight of theextruded/spheronized core.

Illustrative but not limited examples of water insoluble polymers usefulin the XR coating include ethylcellulose powder or an aqueous dispersion(e.g., AQUACOAT® ECD-30), cellulose acetate, polyvinyl acetate(KOLLICOAT® SR 30D, BASF), neutral copolymers based on ethyl acrylateand methylmethacrylate, copolymers of acrylic and methacrylic acidesters with quaternary ammonium groups such as EUDRAGIT® NE, RS andRS30D, RL or RL30D, etc. Illustrative but not limiting water solublepolymers include low molecular weight hydroxypropyl methylcellulose(HPMC), methylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone,and/or polyethylene glycol (PEG) of molecular weight >3000). Theextended release coating is typically applied at a thickness rangingfrom about 1 weight % up to 15 weight % depending on the solubility ofthe active in water and the solvent or latex suspension based coatingformulation used.

The coating compositions used in forming the membranes are usuallyplasticized. Illustrative but not limiting plasticizers includetriacetin, tributyl citrate, triethyl citrate, acetyl tri-n-butylcitrate diethyl phthalate, polyethylene glycol, polypropylene glycol,castor oil, dibutyl sebacate, and/or acetylated monoglycerides, etc. Theplasticizer may comprise about 3 weight % to about 30 weight %, moretypically about 10 weight % to about 25 weight % based on the polymer.The type of plasticizer and its content depends on the polymer orpolymers and nature of the coating system (e.g., aqueous or solventbased, solution or dispersion based and the total solids).

The particle may be primed by applying a thin hydroxypropylmethylcellulose (HPMC)(OPADRY® Clear) film before applying an extendedrelease membrane coating to separate the different membrane layers. HPMCis typically used, but other primers such as hydroxypropylcellulose(HPC) can also be used.

The membrane coatings can be applied to the core using any coatingtechniques used in the pharmaceutical industry. In one embodiment, fluidbed coating is used.

Multi-dose forms may be used, i.e., products in the form ofmulti-particulate dosage forms (pellets, beads, granules, mini-tablets,etc.) or in other forms suitable for oral administration. As usedherein, these terms are used interchangeably to refer tomulti-particulate dosage forms.

An extended release dosage form that includes a mixture of two or morebead populations can be made as follows. An inert particle such as anon-pareil seed, an acidic buffer crystal, or an alkaline buffer crystalis coated with an active and a polymeric binder to form an activeparticle, i.e., immediate release (IR) bead, that may be in the unitdosage form to act as a bolus dose. The active particle is coated with asolution or suspension of a water insoluble polymer or a mixture ofwater soluble and water insoluble polymers to form an extended releasecoated active particle, i.e., extended release (XR). Hard gelatincapsule XR beads alone and optionally, in combination with IR beads at aratio ranging from 95:5 to 70:30 (ER beads: IR beads), are filled toproduce a modified release (MR) capsule exhibiting a target activerelease profile.

In one embodiment, the dosage form has an immediate release portion ofactive dispersed in an oily or lipid system, and another portion that isformulated in a waxy matrix or particles of active coated withhydrophobic carriers. At least 15%-50% of the active is an immediaterelease portion and is in a dosage form suitable for immediate release.The remainder of the tablet capsule, by weight, can include a sustainedrelease formulation of active or a portion of the sustained releaseformulation of active.

The active domperidone or deuterated domperidone may be formulated in alipid-based delivery system. Encapsulating or solubilizing the active inlipid excipients can lead to increased solubilization and absorptionresulting in enhanced bioavailability.

Lipid excipients are commercially available. Because lipids affectabsorption, it is necessary to know lipid excipient characteristics.Factors that determine the choice of excipients for lipid-basedformulations include miscibility, solvent capacity, self-dispersibilityand ability to promote self-dispersion of the formulation, digestibilityand fate of digested products, irritancy, toxicity, purity, chemicalstability, capsule compatibility, melting point, cost, etc.

Dietary oils composed of medium and long chain triglycerides, along withvarious solvents and surfactants, are frequently used to preparelipid-based formulation. Many lipids are amphiphilic, i.e., they have alipophilic portion (fatty acid) and a hydrophilic portion. The meltingpoint increases as the fatty acid chain length increases, but themelting point decreases with an increase in the unsaturation of thefatty acid which also increases susceptibility to oxidation.Solubilizing agents used in lipid-based formulations are provided in thefollowing table:

Solubilizing excipients used in commercially available lipid-based oralformulations

Water-insoluble excipients Triglycerides Surfactants Bees wax Long-chainPolysorbate 20 triglycerides (TWEEN ® 20) Oleic acid HydrogenatedPolysorbate 80 soybean oil (TWEEN ® 80) Soy fatty acids HydrogenatedSorbitanmonolaurate vegetable oil (SPAN ® 20) D-α-Tocopherol Corn oil,Olive oil D-α-Tocopheryl (vitamin E) PEG 1000 succinate (TPGS) Corn oilmono- Soybean oil, Glycerylmonooleate di-triglycerides Peanut oil Mediumchain Sesame oil Polyoxyl 35 (C8/C10) mono castor oil and diglycerides(CREMOPHOR ® EL) Propylene glycol Medium-chain Polyoxyl 40 hydrogenatedesters of triglycerides castor oil fatty acids (CREMOPHOR ® RH40)Caprylic/capric triglycerides Polyoxyl 60 hydrogenated derived fromcoconut oil or castor oil palm seed oil (CREMOPHOR ® RH60) PEG 300 oleicglycerides (LABRAFIL ® M- 1944CS) PEG 300 linoleic glycerides(LABRAFIL ® M- 2125CS) PEG 400 caprylic/capric Glycerides (LABRASOL ®)PEG 1500 lauric glycerides (GELUCIRE ® 44/14)

Triglyceride vegetable oils are the most common lipid excipients. Theyare fully digested and absorbed, eliminating safety issues.Triglycerides are long chain triglycerides (LCT), medium chaintriglycerides (MCT) and short chain triglycerides (SCT). Their solventcapacity for an active is mainly due to the effective concentration ofester groups. MCT have a higher solvent capacity than LCT and are lessprone to oxidation. Oils from different vegetable sources have differentproportions of each fatty acid. The fatty acid composition in variouslipid excipients is shown below.

Composition of fatty acids found in lipid-based excipients: Fatty acidchain length Common Melting (number of carbons) name temperature(° C.) 8 caprylic acid 16.5 10 capric acid 31.6 12 lauric acid 44.8 14myristic acid 54.4 16 palmitic acid 62.9 18 stearic acid 70.1 18linoleic acid 16.0 18 oleic acid −5.0 18 γ-linoleic acid −11.0 18ricinoleic acid 6.0 20 arachidic acid 76.1 22 behenic acid 80.0

D-α-tocopheryl polyethylene glycol 1000 succinate (Vitamin E TPGS) isderived from vegetable tocopherols. It is water soluble and acts asabsorption enhancer for poorly water-soluble drugs. Pure triglyceridesare presented in refined vegetable oils.

Mixed glycerides are obtained by partial hydrolysis of vegetable oils.The triglyceride starting material and the extent of hydrolysisdetermine the chemical composition of the mixed glycerides produced.Medium chain mixed glycerides are not susceptible to oxidation, havegreater solvent capacity, and promote emulsification. These polar oilyexcipients also improve solvent capacity and the dispersibility of theformulation. Examples of polar oils include sorbitan trioleate (SPAN®85) and oleic acid.

Co-solvents, e.g., ethanol, glycerol, propylene glycol, polyethyleneglycols (PEG)-400, etc. increase the solvent capacity of the formulationfor actives and aid the dispersion of systems that contain a highproportion of water soluble surfactants. Practical limits related toco-solvents include precipitation of the solubilized active from thesolvent due to loss of the solvent capacity following dilution,immiscibility of some co-solvents with oils, and incompatibilities oflow molecular weight solvents with capsule shells.

Water insoluble surfactants are lipid excipients with intermediatehydrophilic-lipophilic balance (HLB 8-12) that adsorb at oil-waterinterfaces. Depending on the degree of ethoxylation, they have a finitesolubility in water. They can form emulsions if subjected to shear andmay be referred as being ‘dispersible’ in water. They can form micellesbut cannot self-emulsify due to their insufficiently hydrophilic nature.Oleate esters such as polyoxyethylene (20) sorbitan trioleate(TWEEN®-85) and polyoxyethylene (20) glyceryl trioleate (TAGOT®-TO)exemplify water-insoluble surfactants with HLB 11-11.5. However, a blendof TWEEN®-80 and SPAN®-80 with average HLB of 11 is not similar toTWEEN®-85 in function. A blend of TWEEN®-80 and SPAN®-80 has bothwater-soluble and water-insoluble molecules, but TWEEN®-85 haspredominantly water-insoluble molecules.

Water-soluble surfactants are the most common surfactants forformulating self-emulsifying drug delivery systems. Materials with HLB≥12 can form micellar solutions at low concentrations by dissolving inpure water above their critical micellar concentration (CMC).Water-soluble surfactants are synthesized by PEG with hydrolyzedvegetable oils, or alternatively alcohols can be made to react withethyleneoxide to produce alkyl ether ethoxylate, a commonly usedsurfactant (e.g., cetostearyl alcohol ethoxylate ‘CETOMACROGOL™’). Areaction of sorbitan esters with ethylene oxide produces polysorbates,predominantly ether ethoxylates. CREMOPHOR® RH40 and RH60 (ethoxylatedhydrogenated castor oil) are examples of this type, obtained fromhydrogenation of materials derived from vegetable oils. CREMOPHOR® EL(ethoxylated castor oil), which is not hydrogenated, is also widelyused. CREMOPHOR® enhances absorption by inhibiting the efflux pumps;while the inhibition mechanism is not determined it may be anon-specific conformational change due to penetration of the surfactantmolecules into the membrane, adsorption on to the surface of the effluxpumps, or interaction of molecules with intracellular domains of effluxpump.

Additives may be added to protect the formulation from oxidation.Examples include lipid soluble anti-oxidants such as α-tocopherol,β-carotene, propyl gallate, butylated hydroxyl toluene (BHT), butylatedhydroxyanisole (BHA), etc.

Lipid behavior during formulation is assessed because lipid excipientshave different chemical compositions that lead to broad melting ranges.Thermal properties of lipids, e.g., crystallization temperature, meltingpoint, glass transition temperature, and determination of solid fatcontent of the excipient versus temperature, are evaluated usingdifferential scanning calorimetry (DSC). Lipid organization duringheating or cooling is assessed by hot-stage microscopy. Crystallinity ofa lipid excipient is confirmed by X-ray diffraction (XRD).

High performance liquid chromatography (HPLC) and gas chromatography(GC) can determine the exact composition of ethers, esters, and fattyacid distribution. Other chemical indices include the molecular weightof fatty acids determined from their saponification value, saturation ofhydrocarbon chains determined by an iodine-based assay, oxidativechanges determined by measuring peroxides, free fatty acids measuredfrom acid content, and free hydroxyl groups determined by measuringhydroxyl group content.

The FDA-required dissolution testing does not correlate to the in vivobehavior of lipid-based formulations. Lipids in the gastrointestinaltract are subjected to digestion processes in the presence of lipases(gastric and pancreatic) that also affect the emulsification anddispersion properties of the lipid excipients, leading to alteredsolubilization capacity in vivo. Hence, the digestibility of the lipidexcipients must be considered when selecting lipid-based formulations.Dissolution testing in biorelevant media can assess such effects andpredict in vivo behavior. The effectiveness of self-emulsifyingformulations can be determined by dispersion testing (emulsificationcapacity and particle size). Photon correlation spectroscopy (PCS) orlaser light diffraction can be used to measure the particle size, andvisual observation can help predict emulsification capacity.

Lipid-based excipients enhance the oral absorption of drugs by affectingvarious physiological processes, e.g., stimulating bile flow andpancreatic juice secretion, prolonging gastric emptying, increasing themembrane fluidity, opening of tight junctions, promoting lymphatictransport of drugs thus avoiding first pass metabolism, and inhibitingefflux transporters. To assess these effects various in vitro models areavailable, including intestinal microsomes, Caco-2 cells, everted gutsac using chamber and in situ perfusion assays.

Liposomes may be used; these spherical bilayer structures resemble thecell membrane in their arrangement and are mainly amphiphilicphospholipids (hydrophilic head and hydrophobic fatty acid tail). Whenhydrated, these phospholipids form spherical bilayer structures,oriented with their hydrophobic tails oriented toward the structureinterior and hydrophilic heads oriented toward the structure exterior.Hydrophilic substances can be embedded in the aqueous internal spaces ofthe globules, while hydrophobic active can be embedded within the innerfatty acid layers.

Solid lipid nanoparticles (SLN) may be used. SLN can enhancebioavailability along with controlled and site-specific drug delivery,so are potential carriers for oral intestinal lymphatic delivery. SLNsare typically spherical particles ranging from 10 nm to 1000 nm with asolid lipid core matrix (stabilized by surfactants) that can solubilizelipophilic molecules. Lipids mainly used include monoglycerides such asglycerol monostearate, diglycerides such as glycerol behenate,triglycerides such as tristearin, fatty acids such as stearic acid,steroids such as cholesterol, and waxes such as cetyl palmitate. Oralbioavailability of one drug was improved by formulating aN-carboxymethyl chitosan polymer that coated the drug loaded SLN using amonoglyceride lipid and soya lecithin and poloxamer 188 surfactants(Venishetty et al.)

In spray congealing, also termed spray cooling, molten lipid is sprayedinto a cooling chamber and, on air contact, congeals into sphericalsolid particles. The solid particles are collected from the bottom ofthe chamber and filled into hard gelatin capsules or compressed intotablets. Ultrasonic atomizers generate solid particles in the spraycooling process. Parameters to be considered are the melting point ofthe excipient, the viscosity of the formulation, and the cooling airtemperature inside the chamber to allow instant solidification of thedroplets. Drug granules have been reported to be prepared by meltgranulation using PEG 4000 or Poloxamer 188 as a meltable binder andlactose monohydrate as filler. Microparticles with narrow sizedistribution were reported when stearoyl polyoxylglycerides (GELUCIRE®50/13) were used as an excipient and significantly enhanced solubilityof poorly water soluble drugs (Cavallari et al.).

Melt granulation, also referred to as pelletization, transforms a powdermix of active into granules or pellets. A meltable binder (molten state)is sprayed onto the powder mix in presence of high-shear mixing (‘pumpon’ technique), or the meltable binder is blended with powder mix andmelts due to the friction of particles (solid/semisolid) duringhigh-shear mixing. The melted binder forms liquid bridges between powderparticles and forms small granules that transform into spheronizedpellets under controlled conditions. Depending on powder fineness,15%-25% of the lipid-based binder can be used. Parameters to beconsidered during the process are binder particle size, mixing time,impellar speed, and viscosity of the binder on melting. The dissolutionrate of a drug was improved by formulating melt agglomerates containingsolid dispersions of drug (Seo et al.). Lactose monohydrate wasmelt-agglomerated with a meltable binder, e.g., PEG 3000 of GELUCIRE®50/13 in a high shear mixer. Polyoxylglycerides, partial glycerides orpolysorbates, and lecithins are exemplary lipid excipients used in themelt granulation technique to form self-micro-emulsifying systems.

In embodiments, sustained release matrix tablets may be formulated usinghydrophobic carriers or meltable binders such as stearic acid, carnaubawax, and bees wax, by melt granulation techniques, rendering thecarriers hydrophobic for sustained delivery.

In one embodiment, a pulsatile release form is used. The pulsatilerelease form includes an active core having one or more coatings,referred to as a “coated core” formulation. The coated core may also beused in combination with an amount of the active suitable for immediaterelease.

In one embodiment, an amount of active formulated for immediate releasein combination with at least a second amount of active formulated so thesecond amount has a delay before onset and release of the second portionis or can be extended over time, referred to as a “delayed extendedrelease” formulation. Each of these pulsatile release dosageformulations is further described, with all percentages by weight unlessindicated otherwise.

The “coated core” formulation is an active core of the dosage thatincludes an inert particle such as a commercially available nonpareilsugar sphere. The amount of active in the core is varied depending onthe desired dose to be delivered. In one embodiment, the core containsabout 5% active to about 90% active. In one embodiment, the corecontains about 5% active to about 60% active. The amount of active isbased on the total weight of the core. Those skilled in the art will beable to select an appropriate amount of active for coating orincorporation into the core to achieve the desired dosage form.Typically, the coated core can include about 80 mg, 160 mg, up to about480 mg active. An aqueous or a pharmaceutically acceptable solventmedium may be used for coating the core particles. Any type ofpharmaceutically acceptable inert binder may be used to bind the activeto the inert particle. Water soluble binders may be used. Alcoholsoluble binders may be used. Binders such as polyvinylpyrrolidone (PVP),carboxyalkylcelluloses, polyethylene oxide, polysaccharides such asdextran, corn starch, hydroxypropyl methylcellulose (HPMC (former) orhypromellose (current)), hydroxypropylcellulose, etc. may be used bydispersing them in water at a concentration from about 0.5 weight % to 5weight %. The active can be in this coating formulation in solution formor suspension form. The concentration of active may vary from about 0.1weight % to about 20 weight %, depending on the viscosity of the coatingformulation.

In one embodiment, the active core is prepared by granulation or byextrusion and spheronization. The active, a binder such as PVP, anoptional dissolution rate controlling polymer such as high viscosityHPMC (hypromellose), and optionally other pharmaceutically acceptableexcipients are blended in a high shear granulator (e.g., FIELDER®granulator), or a fluid bed granulator (e.g., GLATT® GPCG granulator),granulated to form agglomerates by adding/spraying a granulating fluid,such as water or alcohol, and dried. The wet mass is extruded andspheronized to produce spherical particles (beads) using an extruder. Inthese embodiments, the drug load may be 90% by weight based on the totalweight of the extruded or granulated core.

In one embodiment, one layer of membrane coating on the particlecontaining the active includes a plasticized enteric polymer, and theother layer includes a mixture of a water insoluble polymer and aplasticized water dispersible/enteric polymer. The water insolublepolymer and the water dispersible polymer are present at a weight ratioof about 10:1 to 1:1, or about 4:1 to 1:1. The total weight of thecoatings is about 15 weight % to 80 weight %, or about 20 weight % toabout 60 weight % based on the total weight of the multiparticulatedosage form.

An intermediate acid-containing membrane is optional. If included, theintermediate acid-containing membrane may include an organic acid, e.g.,fumaric acid, citric acid, succinic acid, tartaric acid, malic acid,maleic acid, etc.; and a binder, e.g., PVP. Water soluble polymers oralcohol soluble polymers are usually used. The weight of thisacid-containing membrane is about 5% to about 20% based on the totalweight of the coated beads. The acid in the acid-containing membranedelays dissolution of the enteric polymer in the inner layer, therebyincreasing the lag time as well as decreasing the rate of release of theactive from the coated bead. The composition of the outer layer of thepolymeric membrane, and the individual weights of the inner,intermediate, and outer membrane layers, are further optimized toachieve pulsatile release profiles for the active based on predicted invitro/in vivo correlations. Thus, the pulsatile release dosageformulation is optimized to release an amount of active after apredetermined time period and/or at a particular point in the digestivetract of the individual administered the formulation.

Examples of enteric polymers include, but are not limited to, thefollowing compounds or composition, either alone or in combination:esters of cellulose and its derivatives (cellulose acetate phthalate,hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcelluloseacetate succinate), polyvinyl acetate phthalate, pH-sensitivemethacrylic acid-methamethacrylate copolymers, and shellac. Thesepolymers may be used as a dry powder or an aqueous dispersion.Methacrylic acid copolymers EUDRAGIT® L100, 5100, L30D are available(Rohm Pharma), cellulose acetate phthalate CELLACEFATE® (EastmanChemical Co.), cellulose acetate phthalate aqueous dispersion AQUATERIC®(FMC Corp.), and hydroxypropyl methylcellulose acetate succinate aqueousdispersion AQOAT® (Shin Etsu K.K.).

Examples of water insoluble polymers include, but are not limited to,the following compounds or composition, either alone or in combination:cellulose derivatives (e.g. ethylcellulose), polyvinyl acetate(KOLLICOAT® SR 30D, BASF), neutral copolymers based on ethyl acrylateand methylmethacrylate, copolymers of acrylic and methacrylic acidesters with quaternary ammonium groups such as EUDRAGIT® NE, RS orRS30D, RL or RL30D, etc.

Membrane coatings can be applied to the core using any pharmaceuticalcoating method known in the art. For example, fluid bed coating may beused.

A pulsatile release dosage formulation may be prepared by (i) coating aninert particle, e.g., a non-pareil seed (sugar sphere), with the activeand polymeric binder, or by preparing the particle containing the activeby granulation and/or extrusion/spheronization to form an activeparticle; (ii) coating the active particle with a plasticized entericcoating, forming the plasticized enteric coated active particle; and(iii) coating the plasticized enteric coated active particle with amixture of a water insoluble polymer and an enteric polymer. The releasecharacteristics can be modulated by interchanging parts (ii) and (iii).An organic acid, as previously described, can be added to the membranebetween parts (ii) and (iii) to further modulate the lag time and activerelease profile from the particle.

In one embodiment, the formulation may use a single form of theparticulate to provide a time-controlled pulsatile release of the activeseveral hours after oral administration, or to target to specificabsorption sites. In one embodiment, dosage forms incorporating themulticoated active containing particles are combined in a compositedosage formulation with an amount of active for immediate release, e.g.,in a gelatin, either hard gelatin or soft gelatin, capsule. Thisembodiment provides a composite dosage form having both an immediaterelease portion and time-controlled pulsatile release portion of active.

The optional immediate release portion and the active of the coated corecan each include about 10 mg, 20 mg, etc. of active, a coated coredosage form of the present invention can contain about 10 to 80 mg ofactive.

In one embodiment, a delayed extended release form is used.

In one embodiment, a dosage form can provide at least a bi-modal bloodprofile of active, e.g., the profile shown in FIG. 2. In thisembodiment, the dosage form contains at least a first amount of activefor immediate release, and a second amount of active for delayedextended release. For example, a first portion of active is immediatelyreleased during the first hour after administration from the inventivedosage form. There is an elapsed time period where substantially noactive is released and/or is capable of entering the circulation, and/oris bioavailable from a second portion of administered active. Then,after another elapsed time, e.g., a few hours, additional active isreleased, and the release of this second portion occurs over an extendedperiod of time, e.g., up to 12 hours after initial administration oreven longer. This release of the second portion typically occurs after alag time during which no active is released, so such dosage forms thatcan exhibit a delay before the initiation of release of an amount ofactive are termed “delayed extended release” dosage forms. Such a dosageform can be administered alone, or it can be administered in combinationwith other dosage forms.

It is desirable for the blood level of active to increase, with theblood concentration corresponding to the amount of active that isbioavailable after the immediate release in the first hour afteradministration. After a time, blood levels of active decreases to lessthan desirable or therapeutic levels. The second portion of active canenter the circulation after the immediate release portion of active hasbeen released. In embodiments, after blood levels of active begin todecrease, the formulation desirably increases and/or maintains bloodlevels at or above about the desired concentration without the need toadminister a second dose of active.

The following example illustrates one embodiment. The firstimmediate-release portion of active has an initial pharmacokineticprofile. Fillers, excipients, etc. can account for the final weightpercent.

Formulations for delayed sustained or extended release are as follows.Each sustained release composition includes an amount of activeformulated to release the active over a period of 4 hours to 12 hours,typically 6 to 12 hours.

Polyalcohols such as mannitol, coagulants such as a POLYOX®, coagulantsand lubricants such as stearic acid are added to yield a granulationthat can provide a delayed and extended release active formulation.Caplets, tablets, or other dosage forms of the delayed releaseformulation are prepared using procedures known in the art, includingencapsulating procedures. Such dosage forms, without more, typicallyexhibit “sustained release” blood profiles, i.e., the dosage formstypically immediately releases active after ingestion and continues torelease active over time. These compositions can also be formulated intoa dosage form, and can exhibit extended release profiles, releasingactive for a period of a few hours up to 12 hours after ingestion.

In one embodiment, the dosage forms formed from the compositions can beoptionally base coated to seal the tablets for subsequent processing.Sealers include, e.g., HPMC, (poly)ethylene glycol (PEG), etc.

In one embodiment, a dosage form is banded with one or more bands of oneor more polymeric materials, as subsequently described and shown in FIG.17. One or more circumferential or other types of bands of polymericmaterial are used, e.g., a relatively insoluble polymeric material thatdoes only minimally or does not erode or degrade during the dispensingperiod. Typical insoluble polymers include the water insoluble polymerspreviously described. The number of bands, the position or spacingbetween bands, and the thickness of the bands can control the rate ofrelease of active. For example, a space of 0.5 mm, 1.0 mm, 1.5 mm, 2.0mm, 2.5 mm, or 3.0 mm can be present between bands if multiple bands areused. For example, each band can be 0.5 mm, 1.0 mm, 1.5 mm, or 2.0 mmwide and have a thickness of about 0.1 micron to 100 micron, or 0.1micron to 50 micron, or 0.1 micron to 20 micron. As shown in FIG. 17, inone embodiment, a caplet has two circumferential polymeric bands, eachband 20 and 30 has a width of about 1 mm and a spacing 40 of about 2 mm.The banded formulation slows the release of the active and extends theperiod of time over which the active can be released and/or enter thecirculation, i.e., to be rendered bioavailable. In embodiments, theband(s) delays the onset of release of active such that there is a lagtime, also termed a delay of onset or delayed release during which noactive is released. A delay of onset can be from 0 hour to 4 hours, ormay be 0 hour to 3 hours, or may be 0.5 hour to 4 hours, or may be 1hour to 2 hours after administration.

The enteric coating may also include other excipients or fillers, e.g.,talc, lactose, dicalcium phosphate, lubricants such as magnesiumstearate, etc.

The banded dosage form can be coated with an enteric coating at a levelof about 2 μg/cm² to 10 μg/cm², typically about 7 μg/cm². The entericcoating delays the onset of active such that there is time during whichno active is released after administration of the dosage form.Typically, after enteric coating, delay of onset of active from a coatedbanded dosage form (e.g., an enteric coated banded caplet) can be from0.5 hour to 4 hours, typically 1 hour to 2 hours.

In one embodiment, an immediate release dose of active previouslydescribed is combined with an enterically coated banded caplet usingmethods known in the art to produce a single composite dosage form,e.g., into a single gelatin capsule. The formulation may be tailored toprovide a specific desired blood profile.

In embodiments, the compositions include at least an immediate releaseformulation and a sustained release formulation, subsequently describedbelow. Sustained release formulations do not typically exhibit a delayedonset of active. Sustained release formulation do not typically exhibita significant time period during which no drug is made bioavailable fromthe dosage form after administration.

In one embodiment, a tablet capsule is a capsule containing a firstportion of active in a tablet form that is formulated for immediaterelease upon ingestion or administration, and at least a second portionof active that is in a tablet form that is formulated for sustainedrelease, i.e., the second portion continues to release an amount ofactive up to 6-12 hours after ingestion. At least 15%-50% of the activeis an immediate release formulation and is in a tablet form and issuitable for immediate release. The remainder of the tablet capsule, byweight, can include a sustained release formulation of active or aportion of the sustained release formulation of active. The tabletcontaining an immediate release formulation of active and the tabletcontaining a sustained release formulation of active may be combined ina single dosage form, e.g. a gelatin capsule, using methods known in theart.

In one embodiment, a granulation caplet is capsule or caplet containinga first portion of a granulation of active that is formulated forimmediate release, and at least a second portion of active that is intablet form that is formulated for sustained release. At least 15%-50%of active is an immediate release formulation and can be in granulesversus a tablet. In one embodiment, at least about 80% of thegranulation capsule includes a composition of active for immediaterelease in a granular form, typically contained in a separate caplet.The remainder of the granulation caplet, by weight, may include asustained release formulation of active, or the granulation caplet mayinclude a portion of the sustained release formulation of active. Thecaplet containing an immediate release formulation of active and thecaplet containing a sustained release formulation of active may becombined in a single dosage form, e.g. a gelatin capsule, using methodsknown in the art.

In one embodiment, a layered tablet contains a tablet having two or morelayers with the active that is formulated for immediate release, and alayer of active that is formulated for sustained release. The layeredtablet contains an amount of active for immediate release uponingestion, and at least a second portion of active that can immediatelyprovide an amount of active for up to 6 hours-12 hours after layeredtablet ingestion. At least 15%-50% of active is an immediate releaseformulation. In one embodiment, at least about 80% of the layered tabletincludes a composition of active for immediate release. The remainder ofthe layered tablet, by weight, may include a sustained releaseformulation of active, or may include a portion of the sustained releaseformulation of active. The formulations can be combined in aconventional manner, e.g. in a tablet press, so that after processing,the final tabletted dosage form has two or more layers, at least a firstlayer containing the immediate release formulation of active and asecond layer containing the sustained release formulation of active.

In one embodiment, the active is least 20% to 30%, 30% to 60%, or 70% byweight of the sustained release composition, with the remaining weightof the composition excipients, e.g., fillers, lubricants, polymers, etc.The polymer can be present from 5% to 20% by weight of the sustainedrelease composition in one embodiment, and from 7% to 10% by weight ofthe sustained release composition in one embodiment, and from 10% to16.5% by weight of the sustained release composition in one embodiment.In one embodiment, the polymer is a cellulosic polymer, e.g. MethocelK4M and is present at about 10% by weight. The sustained releaseformulation can be prepared by direct compression or wet granulation.

The formulation may be compressed into tablets, or may be incorporateddirectly with food. Such compositions should contain at least 0.1% ofactive compound. The percentage of the compositions and preparations mayvary, e.g., about 2% to about 60% of the weight of the unit.

Excipients include, but are not limited to, one or more of apharmaceutically acceptable inert diluent; an assimilable ediblecarrier; a disintegrant to facilitate disintegration, e.g., modifiedcellulose derivatives, modified starch derivatives, etc., noting thatone skilled in the art appreciates that other ingredients includingbinders and lubricants can also affect the dissolution profile of thedosage form; a hard or soft shell gelatin capsule; dicalcium phosphate;a binder such as gum tragacanth, acacia, corn starch, or gelatin; adisintegrating agent such as corn starch, potato starch, alginic acid,etc.; a lubricant such as magnesium stearate; a sweetening agent such assucrose, lactose, or saccharin; a flavoring agent such as peppermint,oil of wintergreen, cherry flavoring; one or more surfactants such asionic, non-ionic, and/or bile salt surfactants, with anionic surfactantsincluding sodium alkyl sulfate (sodium lauryl sulfate) andsulfosuccinate derivatives such as docusate sodium, non-ionicsurfactants including polyoxyethylene sorbitan fatty acid esters(polysorbates) such as TWEEN® 20, TWEEN® 80, TWEEN® 40, SPAN® 20, fattyacid esters of polyethylene glycols such as GELUCIRE® 44/14, GELUCIRE®50/13, saturated polyglycolized (including mono, di or tri)glycerides,medium chain monoglycerides (6-10 carbons) such as glycerylmonocaprylate (IMWITOR® 308), glyceryl monocaproate (CAPMUL® MCM C-8),glyceryl caprylate/caprate (CAPMUL® MCM), polyoxyethylene glycerylcaprylate, and polyoxyethylene glyceryl caproate (LABRASOL®), mediumchain fatty acid esters such as glyceryl tri caprate andglyceryltricarilate (MIGLYOL® 612), block polymers of ethylene oxide andpropylene oxide, polyoxyethylene-polyoxyl propylene block copolymerssuch as Poloxamer 188 (PLURONIC® F-68), Poloxamer 237 (PLURONIC® F-87),Poloxamer 338 (PLURONIC® F-108), Poloxamer 407 (PLURONIC® F-127),Poloxamer 124 (PLURONIC® L-44), polyoxyl stearate-polyethoxylated (40)stearic acid (MYRJ® 52), ethoxylated castor oil-polyethoxylated (60)hydrogenated castor oil (CREMOPHOR® EL), ethoxylated hydrostearic acidpolyethylene glycol 660 hydroxystearate (SOLUTOL® HS 15),polyoxyethylene alkyl ethers (12-18 carbons) such as polyoxyl 20cetostearyl ether (ATLAS® G-3713), polyoxyl 10 oleyl ether (BRIJ® 96,BRIJ® 97, Oleth 10), polyethylene glycol ether (TRITON™ X-100, TRITON™X-114, TRITON™ X-405, TRITON™ N-101) and lecithins such as phospholipids(dimyristoyl DL-alpha-phophatidylcholine), bile salt surfactantsincluding deoxycholic acid, sodium deoxycholate, cholic acid, sodiumtaurocholate; etc. A capsule dosage form may also contain a liquidcarrier. Other materials may be present as coatings or to otherwisemodify the physical form of the dosage form, e.g., tablets, pills, orcapsules may be coated with shellac and/or sugar. A syrup or elixir maycontain the active, sucrose as a sweetening agent, methyl andpropylparabens as preservatives, a dye, and a flavoring agent.

In embodiments, other actives may be included in the formulation.

In one embodiment the dosage forms are a liquid filled soft gel capsulecontaining excipients that have lipids, surfactants and solvents. Thecapsules may contain formulations for immediate release, delayedrelease, sustained release, or controlled release.

The formulation may contain excipients such as one or more fatty acids.The method involves dissolving, melting, or suspending a poorly watersoluble active agent in one or more fatty acids, conjugated fatty acids,(semi-) solid surfactants having a high HLB value, and/or hydrophilicpolymers. Suitable fatty acids include C₁₀-C₁₈ fatty acids, preferablyC₁₆-C₁₈ fatty acids. Suitable conjugated fatty acids include C₁₀-C₁₈fatty acids, preferably C₁₆-C₁₈ fatty acids, conjugated with glycerol(e.g., monoglycerides), monosaccharides, and/or polyethylene glycol(PEG). Suitable hydrophilic polymers include poloxomers and poloxamines.

Suitable fatty acids include C₁₀-C₁₈ fatty acids, more preferablyC₁₆-C₁₈ fatty acids. Exemplary fatty acids include, but are not limitedto, dodecanoic (lauric) acid, tetradecanoic (myristic) acid,hexadecanoic (palmitic) acid, heptadecanoic (margaric) acid,octadecanoic (stearic) acid, eicosanoic (arachidic) acid, docosanoic(behenic) acid, tetracosanoic (lignoceric) acid, hexacosanoic (cerotic)acid, heptacosanoic (carboceric) acid, octacosanoic (montanic) acid,triacontanoic (melissic) acid, dotriacontanoic (lacceroic) acid,tritriacontanoic (ceromelissic) acid, tetratriacontanoic (geddic) acid,and pentatriacontanoic (ceroplastic) acid. The fatty acids can besaturated fatty acids, monounsaturated fatty acids, polyunsaturatedfatty acid, or combinations thereof.

Oils, for example, vegetable oils, such as soybean oil can be used aloneor in combination with the coating materials listed above. Soybean oilcontains 14.4% saturated fatty acids, 23.3% monounsaturated fatty acids,such as oleic acid, and 57.9% polyunsaturated fatty acids, such aslinoleic acid and alpha linoleic acid.

In one embodiment, the fatty acid is covalently coupled to glycerol, amonosaccharide, such as sorbitol or sorbitan, a polyalkylene oxide, suchas polyethylene glycol and polypropylene glycol, or combinationsthereof. These materials are referred to as conjugated fatty acids.Suitable conjugated fatty acids include, but are not limited to,polyethylene glycol esters of fatty acids, such as those availablecommercially under the tradename GELUCIRE®, sorbitan esters of fattyacids, such as sorbitan monostearate, glycerol fatty acid esters of thefatty acids listed above, such as glycerol behenate and glycerylmonostearate, and combinations thereof.

The concentration range of the fatty acid is from about 1% to about 20%by weight of the composition, preferably from about 5% to about 15% byweight of the composition (microparticles and carrier).

The water-insoluble active can be coated with one or more surfactants,alone or in combination with or more fatty acids or conjugated fattyacids and/or one or more hydrophilic polymers. In one embodiment, thesurfactant has an HLB value greater than about 10, greater than about12, greater than about 14, or greater than about 16 (on a scale of1-18). Surfactants having the desired HLB are known in the art. Thesurfactant can be anionic, cationic, or non-ionic. In one embodiment,the surfactant is a non-ionic surfactant.

Examples of such surfactants include, but are not limited to,polysorbate 20, 40, and 80 (marketed under the name TWEEN®),polyoxyethylene monostearate, some sugar esters, such as sucrosemonolaurate, ethoxylated nonyl phenols, alpha olefin sulfonates,ethoxylated tallow amines, ethylene oxide/propylene oxide blockcopolymers, ethoxylated soya amines, fatty acids and alcohols,polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers,and polyoxyethylene stearates.

In one embodiment, the surfactant is a high HLB surfactant containing afatty acid chain. Suitable surfactants include, but are not limited to,polyethoxylated castor oil, polysorbates, polyoxyethylene alkyl ethers,and polyoxyethylene stearates.

Polyoxyethylene castor oil derivatives contain mainly ricinoleylglycerol ethoxylated with 30-50 molecules of ethylene oxide.Polysorbates or polyoxyethylene sorbitan fatty acid esters are a seriesof partial fatty acids esters of sorbitol and its anhydridescopolymerized with approximately 20, 5, or 4 moles of ethylene oxide foreach mole of sorbitol and its anhydrides. The resulting product is amixture of molecules having a wide range of molecular weights.Polyoxyethylene alkyl ethers are a series of polyoxyethylene glycolethers of linear fatty alcohols (n-alcohols), such as lauryl, myristyl,cetyl, and stearyl alcohol. Polyoxyethylene stearates are produced bypolyethoxylation of stearic acid.

Without desiring to be bound by any theory, it is believed that thehydrophilic part of the surfactant enhances the compatibility of theactive agent with the aqueous dissolution media in vitro or in vivo andthat the fatty acid side chain enhances absorption via fatty acidoxidation. During fatty acid oxidation, intracellular Ca′ is consumedwhich results in the widening of gap junctions, allowing passage of theactive agent between cells. Further, such coated particles may be morestable than drug alone, for example, by preventing oxidation of theactive agent.

The concentration of the surfactant is from about 1% to about 50%,preferably from about 5% to about 15% by weight of the composition(microparticles and carrier).

Suitable hydrophilic polymers include, but are not limited to,poloxamers, poloxamines, polyethylene glycols, polyvinyl alcohols,polyvinylpyrrolidone, poly(vinyl alcohol), cellulosic materials, such ashydroxypropylcellulose, hydroxymethylcellulose,hydroxypropylmethyl-cellulose, gelatin, carboxymethyl cellulose, andpolypeptides.

The concentration of the hydrophilic polymer is from about 1 to about50% by weight of the composition, more preferably from about 5% to about15% by weight of the composition. If the hydrophilic polymer is apolyethylene glycol, the concentration is from about 1% to about 80% byweight of the composition, from about 30% to about 60%, from about 35%to about 60%, or from about 40% to about 60% by weight of thecomposition (microparticles and carrier).

In one embodiment, the microparticles are formed by adding a mixture ofthe drug and coating material(s) to a pharmaceutically acceptablecarrier. In one embodiment, the carrier is a hydrophilic or lipophiliccarrier. The resulting particles are suspended in the carrier. Thecarrier may be a single component or a mixture of components. Thecarrier can include solvents, surfactants, or other excipients. Thecarrier materials can alter or modify the rate of release of the drugfrom the microparticles and/or the rate of dissolution of the drug. Thecompositions may exhibit a biphasic release profile due to thecontrolled release properties of the microparticles and the controlledrelease properties of the carrier. Varying the qualitative andquantitative composition of the carrier materials may allow one tomodulate the release profile of the active agent. The carrier maycontain one or more rate controlling excipients which regulate releaseof the active agent. Exemplary rate controlling excipients include, butare not limited to, glyceryl behenate, GELUCIRE®, CREMOPHOR®,hydrogenated vegetable oil, bees wax, cellulosic polymers such ashypromellose, alginates, CARBOPOL® and combinations thereof.

In one embodiment, the carrier is a hydrophilic carrier containing asurfactant having a HLB value greater than about 10, greater than about12, greater than about 14, or greater than about 16, and/or is watersoluble. Exemplary hydrophilic carriers include, but are not limited to,polyethylene glycols, polyoxyethylene 32 lauric glycerides (availablefrom Abitech under the tradename ACCONON® M-44), polyoxyethylene 8caprylicleapric glycerides (available from Abitech under the tradenameACCONON® MC-8) and glycofurol. The hydrophilic vehicle can furthercontain one or more miscible solvents such as glycerin, ethanol,glycofurol, and caprylocaproyl macrogol-8 (available from GattefosseS.A., Saint Priest, France under the tradename LABRASOL®).

In one embodiment, the hydrophilic carrier is water or an alcohol. Inanother embodiment, the carrier is a hydrophilic carrier mixturecontaining polyethylene glycol, and optionally one or more surfactantsand/or water. In a particular embodiment, the hydrophilic carrier is amixture of PEG 400 (e.g., 57% by weight of the composition), water(e.g., 8% by weight of the composition), and TWEEN® 20 (e.g., 10% byweight of the composition). The hydrophilic carrier can also containCREMOPHOR® RH 40. The concentration of the hydrophilic carrier isgenerally from about 50% to about 85% by weight of the composition(microparticles and carrier), preferably from about 70 to about 80% byweight of the composition.

In another embodiment, the carrier is a lipophilic carrier. In apreferred embodiment, the lipophilic carrier has an HLB value of lessthan about 10 and/or is oil soluble. Exemplary lipophilic oily vehiclesinclude, but are not limited to, vegetable oils, medium chain mono-,di-, and triglycerides, glyceryl stearates (available from Sasol underthe tradename IMWITOR®), polyoxyethylated oleic glycerides (availablefrom Gattefosse, SA., Saint Priest, France, under the trandenameLABRAFIL®), mineral oil, mono- and diglyceride emulsifiers such asglyceryl monooleate, glyceryl monocaprate, glyceryl monocaprylate,propylene glycol monocaprylate, and propylene glycol monolaurate(available from Abitec Corp., Columbus, Ohio, under the tradenameCAPMUL®), and dimethylpolysiloxanes such as simethicone.

The concentration of the lipophilic carrier is generally from about 10%to about 50% by weight of the composition (microparticles and carrier),preferably from about 5% to about 35% by weight of the composition.

The compositions described can contain one or more pharmaceuticallyacceptable excipients that are considered safe and effective and may beadministered to an individual without causing undesirable biologicalside effects or unwanted interactions. Exemplary additives include, butare not limited to, solvents, suspending agents, dispersants, buffers,pH modifying agents, isotonicity modifying agents, preservatives,antimicrobial agents, and combinations thereof.

Suitable additives for inclusion in the compositions described hereininclude, but are not limited to, antioxidants (e.g., alpha tocopherols,such as vitamin E acetate, ascorbic acid, butylated hydroxyanisole, andbutylated hydroxytoluene); polar solvents (e.g., water, propyleneglycol, and glycerin); hydrophobic solvents (e.g., corn oil, castor oil,soybean oil, olive oil, fish oil, peanut oil, peppermint oil, saffloweroil, sesame oil, medium chain triglycerides, caprylic triglycerides,capric triglycerides derived from coconut oil or palm seed oil); andviscosity increasing agents (e.g., gelatin, glycerin, carrageenan,colloidal silicon dioxide, hydrogenated vegetable oil; povidone, andpropylene glycol alginate).

The microparticle compositions described herein are generally formulatedfor oral or parenteral administration. Suitable oral dosage formsinclude capsules, such as hard or soft, gelatin or non-gelatin capsules,or oral suspensions or syrups (e.g., FIG. 21). Suitable parenteralformulations include suspensions.

In one embodiment, the microparticle compositions (microparticlessuspended in a hydrophilic or lipophilic carrier) are encapsulated in acapsule, such as a hard or soft capsule. The capsules can be preparedfrom natural and/or synthetic film forming polymers. Suitable naturalfilm forming materials include, but are not limited to gelatin.Non-gelatin capsules include, but are not limited to, capsules made fromcarageenan, shellac, alginates, pectin, and zeins. Suitable syntheticfilm-forming polymers include, but are not limited to, methyl cellulose,hydroxypropyl methyl cellulose acetate succinate, hydroxypropyl methylcellulose phthalate, cellulose acetate phthalate, and acrylates such aspoly (meth)acrylate.

The compositions can also be encapsulated in an enteric capsule, whereinthe capsule is coated with an enteric coating or the capsule shellcontains an enteric polymer as described in WO 2004/030658 to BannerPharmacaps, Inc.

Hard shell capsules are typically prepared by forming the two capsulehalves, filling one of the halves with the fill solution, and thensealing the capsule halves together to form the finished capsule. Softgelatin capsules are typically prepared using a rotary die encapsulationprocess. Such processes are known in the art.

The capsule shell can contain one or more additives. Suitable shelladditives include plasticizers, opacifiers, colorants, humectants,preservatives, flavorings, and buffering salts and acids, andcombinations thereof.

Plasticizers are chemical agents added to gelatin to make the materialsofter and more flexible. Suitable plasticizers include, but are notlimited to, glycerin, sorbitol solutions which are mixtures of sorbitoland sorbitan, and other polyhydric alcohols such as propylene glycol andmaltitol or combinations thereof.

Opacifiers are used to opacify the capsule shell when the encapsulatedactive agents are light sensitive. Suitable opacifiers include titaniumdioxide, zinc oxide, calcium carbonate and combinations thereof.

Colorants can be used to for marketing and productidentification/differentiation purposes. Suitable colorants includesynthetic and natural dyes and combinations thereof.

Humectants can be used to suppress the water activity of the softgel.Suitable humectants include glycerin and sorbitol, which are oftencomponents of the plasticizer composition. Due to the low water activityof dried, properly stored softgels, the greatest risk frommicroorganisms comes from molds and yeasts. For this reason,preservatives can be incorporated into the capsule shell. Suitablepreservatives include alkyl esters of p-hydroxy benzoic acid such asmethyl, ethyl, propyl, butyl and heptyl esters (collectively known as“parabens”) or combinations thereof.

Flavorings can be used to mask unpleasant odors and tastes of fillformulations. Suitable flavorings include synthetic and naturalflavorings. The use of flavorings can be problematic due to the presenceof aldehydes which can cross-link gelatin. As a result, buffering saltsand acids can be used in conjunction with flavorings that containaldehydes in order to inhibit cross-linking of the gelatin.

Medium chain triglycerides may also be used. As used herein, “mediumchain triglycerides” means C6-C12 ester chains formed via theesterification of glycerol with three fatty acids. There are varioussources of medium chain triglycerides, for example coconut oil, palmkernel oils, etc. Fractionated coconut oils are the most commonly usedsources for medium chain triglycerides. Examples of commerciallyavailable medium chain triglycerides may include MIGLYOL® 810, 812 or881 produced by Sasol Germany GMBH, CAPTEX® 300, 355, or 810D producedby the Abitec Corporation, NEOBEE® M5 by the Stepan Company, CRODAMOL®GTC/C produced by Croda Inc, and LABRAFAC® Lipophile WL 1349 produced bythe Gattesfosse Group. In one exemplary embodiment, the medium chaintriglyceride may comprise CAPTEX® 355, which is a triglyc-eride ofcaprylic (C8)/capric (C10) acid.

Various amounts of the medium chain triglycerides may be included in thepharmaceutical formulation. In one or more embodiments, thepharmaceutical formulation may comprise about 50% to about 95% by weightmedium chain triglycerides, or about 85% to about 95% by weight mediumchain triglycerides. Moreover, in exemplary embodiments, thepharmaceutical formulation may include from about 100 mg to about 300mg, or from about 200 mg to 300 mg of the weight medium chaintriglycerides, or about 225 mg to 275 mg of the weight medium chaintriglycerides, or about 250 mg of the weight medium chain triglycerides.

Similar to medium chain triglycerides, “medium chain monoglycerides” and“medium chain diglycerides” are C6-C12 ester chains formed via theesterification of glycerol with one fatty acid or two fatty acids,respectively. Examples of commercially available medium chainmono/diglycerides may include the CAPMUL® products produced by Abitec.It is also contemplated to use medium chain mono/diglyceride compoundsthat also include medium chain triglycerides, for example, thecommercially available IMWITOR® compositions produced by Sasol.

In exemplary embodiments, the medium chain mono/diglycerides maycomprise CAPMUL® MCM, which include medium chain mono/diglycerides ofcaprylic (C8)/capric (C10) acid. While all grades of the CAPMUL® MCMproduct line are suitable for use in the present invention, e.g.,national formulary (NF) grade or CAPMUL® MCM EP, it may be desirable touse to EP grade as it includes 3% glycerol, whereas the NF gradeincludes 7% glycerol.

In accordance with one or more embodiment, the pharmaceuticalformulation may comprise about 5% to about 25% by weight medium chainmono/diglycerides, or from about 5% to about 15% by weight medium chainmono/diglycerides. Moreover, in exemplary embodiments, thepharmaceutical formulation may include about 20 mg to 50 mg of theweight medium chain mono/diglycerides, or about 25 mg to 30 mg of theweight medium chain mono/diglycerides, or about 25 mg of the weightmedium chain mono/diglycerides.

Without being bound by theory, the mixture of medium chain triglyceridesand medium chain mono/diglycerides is important for the bioavailabilityof the active ingredient inside the liquid-filled bard gel capsuleformulation. While a soft gel capsule may only include medium chainmono/diglycerides, a hard gelatin capsule with only medium chainmono/diglycerides may not provide the requisite physical stability ofthe finished dosage forms. However, a mixture of medium chaintriglycerides and medium chain mono/diglycerides inside a hard gelatincapsule may achieve the desired product stability, solubility andbioavailability of the active pharmaceutical ingredient. Consequently,in accord with the invention, the ratio by weight of the medium chaintriglycerides to the medium chain mono/diglycerides facilitates thesolubility and stability of the active pharmaceutical ingredient (e.g.,dutasteride) within the non-emulsified mixture prior to and after theaddition of the mixture into the capsule. The medium chain triglyceridesand medium chain mono/diglycerides may be present at a ratio by weightof from about 10:1 to about 5:1, or from about 10:1 to about 7:1.

In addition to the above components, other excipients known to oneskilled in the art may be used, e.g., excipients used in the oralcomposition may be diluents, binders, lubricants, disintegrants,flavoring agents, coloring agents, stabilizers, glidants, plasticizers,preservatives and sweeteners.

Diluents may include liquid diluents such as any long chain triglyceride(arachis oil, almond oil, peanut oil, palm oil, palm kernel oil,blackcurrent seed oil, rice bran oil, soybean oil, canola oil, corn oil,coconut oil, cotton seed oil, castor oil, olive oil, Linn oils (Neem),sesame oil, primrose oil, vegetable oil, Lipex 108 (Abitec), wheat germoil, fish oil, rapeseed oil, sunflower oil and saffola oil. Inalternative embodiments, it is contemplated that other diluents may beused, for example, diluents selected from calcium-aluminum silicates(SIPERNAT® 106PQ), calcium carbonate, calcium phosphate dibasic, calciumphosphate tribasic, calcium sulfate, microcrystalline cellulose,microcrystalline silicified cellulose, powdered cellulose, dextrates,dextrose, fructose, lactitol, lactose anhydrous, lactose monohydrate,lactose dihydrate, lactose trihydrate, mannitol sorbitol, starch,pregelatinized starch, sucrose, talc, xylitol, maltose maltodextrin,maltitol, silicon dioxide, HPMC and combinations thereof.

The formulation includes the route of administration, type ofpreparation, non-active ingredients release of active, stability,scale-up, new processes for preparation of active, new processes forformulation.

In vivo performance evaluation includes pharmacokinetic data such aspK/pD such as T_(max), C_(max), plasma concentration curve, efficacy,side effects, etc.

Other release profiles include but are not limited to controlled,enteric, sustained, fast, multi-phasic, etc.

Other known and to be determined uses of the inventive formulations ofdomperidone and deuterated domperidone are encompassed by the invention.

Each of the references previously cited as well as listed below isincorporated by reference herein in its entirety:

-   Chang and Robinson, chapter 4: Sustained Drug Release from Tablets    and Particles Through Coating, Pharmaceutical Dosage Forms: Tablets,    vol. 3, Eds. Lieberman, Lachman, and Schwartz, Marcel Dekker, Inc.,    1991.-   Campbell and Sackett, Chapter 3: Film coating, Pharmaceutical Unit    Operations: Coating, edited by Avis, Shukla, and Chang, Interpharm    Press, Inc., 1999.-   Youssef et al., Identification of Domperidone Metabolites in Plasma    and Urine of Gastroparesis Patients with LC-ESI-MS/MS, Xenobiotica    43 (2013) 1073-1083.-   Michaud et al., An Improved HPLC Assay with Fluorescence Detection    for the Determination of Domperidone and Three Major Metabolites for    Application to in vitro Drug Metabolism Studies, J. Chromatogr. B,    852 (2007) 611-616.

The disclosed compositions include a therapeutic amount of domperidoneor deuterated domperidone or a pharmaceutically acceptable salt thereofand at least one excipient. The excipient may, e.g., facilitate deliveryof the active agent. As previously disclosed, other active agents may beincluded, e.g., analgesic agents, anesthetic agents, antioxidants,antimicrobial agents, antifungal agents, vitamins, etc.

One or more analgesic agents can be included in the pharmaceuticalcompositions to provide relief from pain that may result fromgastroparesis. Examples of analgesics include, but are not limited to,simple analgesics such as paracetamol or aspirin; non-steroidalanti-inflammatory drugs (NSAIDS) such as ibuprofen, diclofenac sodium,or naproxen sodium; and/or opioids such as codeine, dihydrocodeine,codeine phosphate, fentanyl, methadone, tramadol hydrochloride,dextropropoxyphe hydrochloride, morphine, oxycodone, buprenorphine, orpethidine hydrochloride.

One or more anesthetic agents can be included in the pharmaceuticalcompositions to induce temporary and reversible absence of painsensation caused by gastroparesis. Examples of anesthetics include, butare not limited to, one or more of lidocaine, benzocaine, bupivacaine,articaine, cocaine, etidocaine, flecamide, mepivacaine, pramoxine,prilocalne, procaine, chloroprocaine, oxyprocaine, proparacaine,ropivacaine, tetracaine, dyclonine, dibucaine, chloroxylenol,cinchocaine, dexivacaine, diamocaine, hexylcaine, levobupivacaine,propoxycaine, pyrrocaine, risocaine, rodocaine, and pharmaceuticallyacceptable derivatives thereof.

One or more antioxidants can be included in the pharmaceuticalcompositions. Examples of antioxidants include, but are not limited to,ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene,diethylenetriaminepentaacetic acid (DTPA), edetates (EDTA),monothioglycerol, sodium ascorbate, sodium formaldehyde sulfoxylate,sodium metabisulfite, butylated hyrodxytoluene (BHT), butylatedhydorxyanisole (BHA), sodium bisulfate, triglycolamate, vitamin E or aderivative thereof, and propyl gallate.

In one embodiment, domperidone or deuterated domperidone, and optionallyany other agent, is incorporated into or on particles, includingnanoparticles. Domperidone or deuterated domperidone particles may besuspended or dispersed in an aqueous medium. The particle size thus mayrange from microparticles (μm) to nanoparticles (nm).

A human or other mammal afflicted with gastroparesis, or othergastrointestinal motility disorders, can be treated through periodicadministration of the inventive disclosed pharmaceutical compositionsone or more times daily. The pharmaceutical agents, includingdomperidone or deuterated domperidone and any supplemental therapeuticagent, is present in the composition in an amount constituting atherapeutically effective dose. A therapeutically effective dose is anamount of the pharmaceutical agent that, upon treatment, results in adegree of reduction of symptoms relative to the pre-dose status of suchsymptoms.

The pharmaceutical compositions can be administered one to four timesper day.

In one embodiment, domperidone or deuterated domperidone is administeredin the range between 0.5 mg to 100 mg, or in the range between 0.05% to10.0%, or in the range between 0.07 mg/kg to 1.43 mg/kg. In oneembodiment, domperidone or deuterated domperidone is administered in therange between 1 mg to 60 mg, or between 0.1% to 6.0%, or between 0.014mg/kg to 0.86 mg/kg. In one embodiment, domperidone or deuterateddomperidone is administered in the range between 2.0 mg to 30 mg, orbetween 0.2% to 3.0%, or between 0.028 mg/kg to 0.43 mg/kg. In oneembodiment, domperidone or deuterated domperidone is administered in therange between 0.5 mg to 120 mg, or between 0.05% to 12.0%, or between0.07 mg/kg to 0.71 mg/kg. In one embodiment, domperidone or deuterateddomperidone is administered in the range between 2.0 mg to 40 mg, orbetween 0.2% to 4.0%, or between 0.028 mg/kg to 0.57 mg/kg. All %designations are w/w.

The formulations can also include excipients. Exemplary excipientsinclude, but are not limited to, binders, fillers, solvents, lubricants,antioxidants, buffering agents, salts, surfactants, vitamins, pigments,flavorants, disintegrating agents, and/or plasticizers.

Solid excipients can be added to the pharmaceutical composition and thenground and formed into tablets. Exemplary solid excipients include, butare not limited to, sugars, including lactose, sucrose, sucralose,mannitol, or sorbitol; cellulose-based materials, such as corn starch,wheat starch, rice starch, potato starch, gum tragacanth, gelatin,methyl cellulose, polyvinylpyrrolidone, hydroxypropylmethyl-cellulose,and/or sodium caboxymethyl cellulose. Excipients to facilitate tabletdisintegration upon ingestion include, but are not limited to, agar,alginic acid and/or salts thereof, mannitol, microcrystalline cellulose,maize starch, citrus pulp, sodium lauryl sulfate, bentonite, sodiumstarch glycolate, calcium carboxymethyl-cellulose, clays, aligns, gums,wood cellulose, powdered natural sponge, and/or cation-exchange resins.

The composition can include other excipients and additives to modify oneor more composition characteristics, such as coating ability, viscosity,palatability, etc. Excipients to improve palatability may include, butare not limited to, sugars such as lactose, sucrose, sucralose,dextrose, mannitol, or sorbitol; natural sweeteners such as honey;cellulose based additives such as corn starch, wheat starch, ricestarch; other sweeteners such as alitame, aspartame, cyclamic acid andsalts thereof, dihydrochalcones, glycyrrhizinates, monellin, sodiumsaccharine, thaumatin, or acesulfame potassium; and/or other sweetenersor flavorants.

Optional viscosity modifier excipients can be added to a liquidformulation of the composition to alter the composition's flowcharacteristics. Flow characteristics can be modified for incorporationinto a specific device or application mechanism to apply the compositionto a treatment site. Exemplary viscosity modifying excipients include,but are not limited to, glycerine, a carbomer homopolymer, a carbomercopolymer, acacia (gum arabic), agar, aluminum magnesium silicate,sodium alginate, sodium stearate, bladderwrack, bentonite, carbomer,carrageenan, ceratonia, chondrus, dextrose, furcellaran, gelatin, Ghattigum, guar gum, sterculia gum, gum tragacanth, xanthum gum, hectorite,lactose, maltodextrin, mannitol, sucrose, sorbitol, honey, maize starch,wheat starch, rice starch, potato starch, polyethylene glycols,cellulose, ethyl cellulose, ethylhydroxyethyl cellulose, ethylmethylcellulose, methyl cellulose, hydroxyethyl cellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, poly(hydroxyethyl methacrylate),oxypolygelatin, pectin, polygeline, propylene carbonate, methyl vinylether/maleic anhydride copolymer (PVM/MA), poly(methoxyethylmethacrylate), poly(methoxyethoxyethyl methacrylate), hydroxypropylcellulose, hydroxypropylmethyl-cellulose, carboxymethyl-cellulose (CMC)(including salts thereof), silicon dioxide, polyvinylpyrrolidone (PVP),and/or SPLENDA®.

The pharmaceutical compositions can also include one or more binders,fillers, solvents, lubricants, antioxidants, buffering agents, salts,surfactants, vitamins, pigments, flavorants, disintegrating agents,and/or plasticizers. Exemplary binders include, but are not limited to,any of the previously disclosed starches such as maize starch, wheatstarch, rice starch, and/or potato starch, cellulosic derivatives suchas methylcellulose, carboxymethyl cellulose, hydroxyethyl cellulose,hydroxy-ethylmethyl cellulose, etc., POLYOX™ polyethylene oxide polymersof any molecular weight or grade, irradiated or not,polyvinylpyrrolidone (PVP), AVICEL® microcrystalline cellulose powder,etc. Exemplary fillers include, but are not limited to, any of thepreviously disclosed sugars and starches, cellulose, calcium salts,diatomaceous earth, and/or titanium dioxide. Exemplary buffers include,but are not limited to, acetate buffers, citrate buffers, and/orphosphate buffers.

Surfactants added to the pharmaceutical composition can be anionic,cationic, non-ionic, or zwitterionic. Exemplary surfactants include, butare not limited to, sodium alkyl sulfates (e.g. sodium dodecyl sulfate(SDS)), quaternary ammonium and pyridinium cationic surfactants,polysorbates, sorbitan esters, bile acids, bile acid salts, nonoxynol orpolyoxytheylene glycol fatty acid esters, and/or poloxamers. Exemplarylubricants include, but are not limited to, talc, hydrogenated fattyoils, magnesium stearate, calcium stearate, and/or stearic acid.Flavorants can include natural or synthetic flavors. Plasticizersinclude, but are not limited to, glycerol and sorbitol.

Pharmaceutical compositions for treating gastroparesis and othergastrointestinal motility disorders with domperidone or deuterateddomperidone can be formulated for topical oral administration to mucosalsurfaces. Mucoadhesive delivery technologies provide safe andefficacious delivery of domperidone or deuterated domperidone throughthe oral mucosa. These mucoadhesive delivery technologies include allmethods of diffusion in the oral mucosa: (i) passive diffusion includingtrans-cellular (through cells) and para-cellular (where material passesthrough lipid rich domains around the cells), (ii) carrier mediatedtransport, and (iii) endocytosis/exocytosis where material is activelytaken up and excreted by cells via the endocytic pathway. Bioadhesion,also known as mucoadhesion, defines the ability of a biological orsynthetic material to adhere or “stick” to a mucous membrane, resultingin adhesion of the material to the tissue for a protracted time. Thisability provides application in drug delivery and enhanced drugbioavailability that results from the lengthened time in which thebioadhesive dosage form is in contact with the absorbing tissues, versusa standard dosage form. For a material to be bioadhesive, it mustinteract with mucus. Mucus is a highly hydrated, viscous anionichydrogel layer protecting the mucosa. Mucin is composed of flexibleglycoprotein chains.

In this embodiment, the pharmaceutical composition includes atherapeutic amount of domperidone or deuterated domperidone and anyoptional other active agent if present, and at least one excipient thatcan include a mucoadhesive or bioadhesive to increase the duration ofcontact between the pharmaceutically active agent and the oral mucosa,and to increase mucosal absorption of the active agent. The absorptionsurface is the tissue surface underneath the oral mucosa to which thepharmaceutically active agent is intended to be applied. Thepharmaceutical compositions can be applied in the form of ointments,creams, lotions, gels, powders or pastes, and can be applied totreatment sites with or without occlusion by films or tapes or byspecific adhesive bandages. The compositions can also include a vehicleto facilitate administration of the composition to the oral mucosa.

Exemplary mucoadhesive or bioadhesive excipients include, but are notlimited to, polymers that are natural, synthetic or biological; lipids,phospholipids, etc. Examples of natural and/or synthetic polymersinclude cellulosic derivatives such as methylcellulose, carboxymethylcellulose, hydroxyethyl cellulose, hydroxyethylmethyl microcrystallinecellulose, etc.; natural gums such as guar gum, xanthan gum, locust beangum, karaya gum, vee-gum, etc.; polyacrylates such as CARBOPOL®polymers, polycarbophil, etc.; alginates, thiol-containing polymers,polyoxyethylenes, polyethylene glycols (PEG) with molecular weightspreferably between 1000 and 40,000 Da whether linear or branched,dextrans with molecular weights preferably between 1000 and 40,000 Da ofany source, block copolymers e.g., combinations of lactic acid andglycolic acid such as PLA, PGA, PLGA of various viscosities, molecularweights and lactic-to-glycolic acid ratios; polyethyleneglycol-polypropylene glycol block copolymers of any number andcombination of repeating units such as PLURONIC® block copolymers,TETRONIC® block copolymers, or GENAPOL® block copolymers, combination ofthe above copolymers either physically or chemically linked units, e.g.,PEG-PLA or PEG-PLGA copolymer mixtures. The bioadhesive material may beselected from polyethylene glycols, polyoxyethylenes, polyacrylic acidpolymers, such as CARBOPOL® polymers (such as CARBOPOL® 71G, 934P, 971P974P) and polycarbophils (such as NOVEON® AA-1, CA-1, and CA-2polycarbophils), cellulose and its derivatives, polyethylene glycol,CARBOPOL® polymers, and/or a cellulosic derivative or combination; asoluble polyvinylpyrrolidone polymer (PVP), a carbomer homopolymer, acarbomer copolymer, one or more maltodextrin, alginate, a cross-linkedalginate gum gel, a water-swellable but water-insoluble fibrouscross-linked carboxy-functional polymer, a hydrophilic polysaccharidegum, thiomers e.g., thiolated chitosan, thiolated polycarbophil,thiolated alginate, thiolated cellulose derivatives, thiolatedcarboxymethyl cellulose, thiolated polyacrylic acid, or thiolatedpolyacrylates; lectin, hydroxypropyl methyl cellulose (HPMC), cellulosederivatives, HPMA copolymers, a water-dispersible polycarboxylated vinylpolymer, cationic polymers, non-ionic polymers, or anionic polymers.Cationic polymers include but are not limited to chitosan (Wella “lowviscosity”), chitosan (Wella “high viscosity”), chitosan (Dr. Knapczyk),daichitosan H, daichitosan VH, Sea Cure 240, Sea Cure 210+, chitosan(Sigma), Polycarbophil/Diachitosan VH blend, DEAE-dextran, andaminodextran. Non-ionic polymers include but are not limited toScleroglucan, He-starch, and HPC. Anionic polymers include but are notlimited to carboxymethylcellulose (CMC) low, medium, or high viscosity),pectin, xanthan gum, and/or polycarbophil. In one embodiment themucoadhesive agent is a CARBOPOL® polymer and/or a cellulosicderivative.

Chitosan, due to its mucoadhesive character (Lehr et al. 1992) andfavorable toxicological properties, is an absorption enhancer acrossintestinal epithelia. Chitosan glutamate reduced transepithelialelectrical resistance (TEER) in vitro of a cultured intestinalepithelial cell line (Caco-2) (Borchard et al., 1996) and increased thetransport of hydrophilic molecules such as [14C]mannitol, molecularweight (MW) 182.2 and a fluorescein-dextran (MW 4400) significantly inCaco-2 cell monolayers (Artursson et al. 1994; Borchard et al., 1996;Schipper et al., 1996). Similarly, transport of the peptide drug9-desglycinamide, 8-arginine vasopressin (DGAVP, MW 1412) increasedmarkedly after coadministration with chitosan glutamate in Caco-2 cellmonolayers (Luessen et al. 1997). Chitosan salts such as chitosanglutamate and chitosan hydrochloride are used in vivo as absorptionenhancers for peptide drugs. Nasal application of insulin with chitosanglutamate significantly reduced blood glucose levels of rats and sheep(Illum et al. 1994), and intraduodenal application of buserelin (MW1299.5) and chitosan hydrochloride in a gel formulation increased theabsolute bioavailability of buserelin from 0.1±0.1 to 5.1±1.5% (Luessenet al. 1996a). These increases in absorption could be attributed to theeffect of chitosan on the integrity of the epithelial tight junctions.Tight junctions play a crucial part in maintaining the selective barrierfunction of cell membranes and in sealing cells together to form acontinuous cell layer through which even small molecules cannotpenetrate. However, tight junctions are permeable to water,electrolytes, and other charged or uncharged molecules up to a certainsize (Madara 1989; Wilson and Washington 1989). Tight junctions areknown to respond to changes in calcium concentrations, cyclic AMP(cAMP), osmolarity, pH, and the status of the cytoskeleton (Cereijido etal., 1993).

Chitosan salts are proposed to open tight junctions in a concentration-and pH-dependent way to allow paracellular transport of largehydrophilic compounds. The increase in the transport of these compoundscould be attributed to an interaction of a positively charged aminogroup on the C-2 position of chitosan with negatively charged sites onthe cell membranes and tight junctions of the mucosal epithelial cellsto allow opening of the tight junctions. It is known that chitosanglutamate induces changes in F-actin distribution (Artursson et al.1994). It is also known that pharmacological agents that interact withcytoskeletal F-actin simultaneously increase paracellular permeability(Meza et al. 1982). This agrees with the hypothesis that F-actin isdirectly or indirectly associated with the proteins in the tightjunctions such as ZO-1 (Madara 1987). Schipper et al. (1997) have shownthat chitosan induces a redistribution of cytoskeletal F-actin and thetight junction protein ZO-1. Confocal laser scanning microscopy hasconfirmed that chitosan is able to open the tight junctions to allowparacellular transport of large hydrophilic compounds (Borchard et al.1996; Schipper et al. 1997). Mucoadhesion may play an additional role inthis process by increasing the residence time of the drugs on the cellsurfaces.

In embodiments, the mucoadhesive/bioadhesive excipient is typicallypresent in a range of about 1% to about 50% w/w, or in a range of about1% to about 40% w/w, or in a range of about 2 to about 30% w/w. A singlemucoadhesive or bioadhesive or combinations may be used. Bioadhesionincreases residence time of a dosage form at the absorption site, andthereby may result in increased drug bioavailability. Use of amucoadhesive facilitates prolonged contact between the pharmaceuticalcomposition and the oral mucus membrane. Upon contact of thepharmaceutical composition with the mucus membrane, moisture in themucus plasticizes the mucoadhesive, which may then consolidate with themucus membrane by forming weak bonds with the glycoproteins in the mucusand/or mechanically interlocking with the glycoproteins and lipids inthe mucus. The mucoadhesive may increase the residence time of contactof the pharmaceutically active agent and the absorption surface and mayfacilitate absorption of the pharmaceutically active agents by theabsorption surface.

The following examples are not limiting. Examples 1-5 are according tosynthesis Scheme 1. Examples 6-8 are according to synthesis Scheme 2.

From synthesis scheme 1

EXAMPLE 1: PREPARATION OF2,3-DIHYDRO(4,5,6,7-D₄)-1H-1,3-BENZODIAZOL-2-ONE

A 100 mL round-bottomed flask equipped with a stir bar and nitrogenin/outlet was charged with (D₄)benzene-1,2-diamine (1 eq, 2 g, 17.83mmol) and 30 ml of dry DMF then agitated under nitrogen to dissolvebefore charging 1-(1H-imidazole-1-carbonyl)-1H-imidazole (1 eq, 2.89 g,17.83 mmol) and stirring at RT for 22 h. The solvent was evaporatedunder vacuum to afford a yellow dense oil which was diluted in a minimalamount of dichloromethane (DCM) to crystallize. The desired solid wascollected by vacuum filtration, washed with DCM and dried under vacuumto yield 2.09 g (15.13 mmol, 85%) of the desired product.

EXAMPLE 2: PREPARATION OF TERT-BUTYL2-OXO-2,3-DIHYDRO(4,5,6,7-D₄)-1H-1,3-BENZODIAZOLE-1-CARBOXYLATE

To a 100 mL three-neck round-bottomed flask equipped with a stir bar andnitrogen in/outlet was charged2,3-dihydro(4,5,6,7-D₄)-1H-1,3-benzodiazol-2-one (1 eq, 2.09 g, 15.13mmol) and 40 ml of dry DMF. To this stirred solution, sodium hydride(1.1 eq, 197 mg, 8.200 mmol) was added portion-wise and the reaction wasleft under the same conditions for 1.5 h. After this period,di-tert-butyl dicarbonate (1 eq, 3.30 g, 15.13 mmol), dissolved in 8 mlof dry DMF, was added dropwise and left to react for 3 h. The reactionwas complete and it was treated with a saturated solution of NH₄Cl,followed by dilution with H₂O and extraction with 4×50 ml of EtOAc. Theorganic fractions were combined, dried over Na₂SO₄, filtered andconcentrated to dryness under vacuum. The crude material thus obtainedwas purified through a silica gel chromatography (Biotage ISOLERA™,KP-Sil 50 g cartridge, eluting with a gradient of Cy:EtOAc from 90:10 topure AcOEt) to yield 3.134 g (13.15 mmol, 87%) of desired compound.

EXAMPLE 3: PREPARATION OF TERT-BUTYL3-(3-CHLOROPROPYL)-2-OXO-2,3-DIHYDRO(D₄)-1H-1,3-BENZODIAZOLE-1-CARBOXYLATE

To a three-necked round-bottomed flask was charged tert-butyl2-oxo-2,3-dihydro-1H-1,3-benzodiazole-1-carboxylate (1 eq, 3.134 g,13.15 mmol) in 60 ml of dry DMF and stirred at room temperature. To thissolution, potassium carbonate (3 eq, 5.452 g, 39.45 mmol) was addedportion-wise and left under the same conditions for 30 minutes. Afterthis, 1-bromo-3-chloropropane (1 eq, 1.300 ml, 13.15 mmol) was added tothe solution and stirred at room temperature overnight. The reaction wasthen quenched by diluting with ethyl acetate (EtOAc) and H₂O. The layerswere separated and the aqueous phase was extracted with 3×25 ml of EtOAcand the organic layers were combined, washed with brine, dried overNa₂SO₄, filtered and concentrated to dryness under vacuum. The crudematerial, thus obtained, was purified using a silica gel chromatography(Biotage ISOLERA™, KP-Sil 50 g cartridge, eluting with a gradient ofCy:EtOAc from 90:10 to Cy:EtOAc from 1:1) to give the desired compound(3.929 g, 12.48 mmol, 95%).

EXAMPLE 4: PREPARATION OF1-(3-IODOPROPYL)-2,3-DIHYDRO(4,5,6,7-D₄)-1H-1,3-BENZODIAZOL-2-ONE

A 250 mL round-bottomed flask was charged with tert-butyl3-(3-chloropropyl)-2-oxo-2,3-dihydro(D₄)-1H-1,3-benzodiazole-1-carboxylate(1 eq, 3.929 g, 12.48 mmol), dissolved in 100 ml of acetonitrile, andstirred at room temperature. Sodium iodide (4.5 eq, 8.417 g, 56.16 mmol)was added portion-wise and the reaction was refluxed overnight. Aftercooling to room temperature the reaction was filtered and the solventwas removed under vacuum. The crude material, thus obtained, waspurified with a silica gel chromatography (Biotage ISOLERA™, KP-Sil 100g cartridge, eluting with a gradient from pure DCM to pure DCM:MeOH/1:1)to give the desired compound (3.631 g, 11.86 mmol, yield=95%).

EXAMPLE 5: PREPARATION OF1-{3-[4-(5-CHLORO-2-OXO-2,3-DIHYDRO-1H-1,3-BENZODIAZOL-1-YL)PIPERIDIN-1-YL]PROPYL}-2,3-DIHYDRO(4,5,6,7-D₄)-1H-1,3-BENZODIAZOL-2-ONE(COMPOUND 2)

A 500 mL round-bottomed flask was charged with5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (1.2 eq, 3.582 g,14.23 mmol) then dissolved in 250 ml of dry THF and 25 ml of dry DMF.This solution was stirred under nitrogen at room temperature and asolution of1-(3-iodopropyl)-2,3-dihydro(4,5,6,7-D₄)-1H-1,3-benzodiazol-2-one (1 eq,3.631 g, 11.86 mmol) in 120 ml of dry THF was added drop-wise over 10minutes. The resulting yellow solution was stirred for 2 h beforecharging potassium carbonate (1.5 eq, 2.458 g, 17.79 mmol) and stirringat RT for 48 h until the yellow color disappeared. The reaction wasfiltered and the solid was washed with EtOAc and the filtrate wasconcentrated to dryness under vacuum. The crude material thus obtainedwas passed through a silica gel chromatography (Biotage ISOLERA™, KP-Sil340 g cartridge, eluting with a gradient of DCM:MeOH from 98:2 toDCM:MeOH/1:1). At the end of the purification process, 3.245 g (7.45mmol, 64%) of desired compound 2 was obtained as a white crystallinesolid.

From synthesis scheme 2

EXAMPLE 6: PREPARATION OF 4,5,6,7-TETRADEUTERO-2-ETHOXY-1H-BENZIMIDAZOLE(COMPOUND 15)

To a round-bottomed flask equipped with a stir bar, thermocouple,condenser and nitrogen in/outlet was charged 6.5 g (58 mmol, 1 eq) of2-amino-3,4,5,6-tetradeuteroaniline, which was suspended in 13.3 mL(12.25 g, 63 mmol, 1.1 eq) of tetraethyl orthocarbonate and 0.3 mL (0.35g, 5.8 mmol, 0.1 eq) of acetic acid. Absolute ethanol 19.5 mL was addedto the suspension, and the resultant mixture was heated to reflux whereit was stirred for one hour until complete by HPLC analysis. The orangesolution was distilled to remove 20.5 mL of ethanol before a solution of13 mL of saturated sodium carbonate and 26 mL of water was added at justbelow reflux to precipitate the product. Once addition was complete thesuspension was cooled to room temperature where the solid was collectedby vacuum filtration. The resultant wet-cake was washed with water (26mL), then dried in a vacuum oven overnight at 50° C. to yield 9.34 g(97.4%) of the desired product, with >99.5% purity by HPLC.

EXAMPLE 7: PREPARATION OF1-(3-CHLOROPROPYL)-4,5,6,7-TETRADEUTERO-2-ETHOXY-BENZIMIDAZOLE (COMPOUND16)

To a round-bottomed flask equipped with a stir bar, nitrogen in/outletand condenser was charged 9.2 g (55.3 mmol, 1.0 eq) of Compound 15,potassium carbonate (15.3 g, 110.1 mmol, 2.0 eq),1-bromo-3-chloro-propane (8.21 mL, 83.1 mmol, 1.5 eq) and 55 mL ofmethyl isobutyl ketone (MIBK). The resultant suspension was heated toreflux and stirred for 3 h until complete by HPLC analysis. Aftercooling to room temperature, 36.8 mL of water was added and the mixturestirred to dissolve salts before separating the phases. The aqueouslayer was extracted with MIBK (1×36.8 mL), the organic layers werecombined then concentrated to an oil. MIBK (36.8 mL) was added to theoil and concentrated again. This procedure was repeated until 1H NMRanalysis indicated <1 mol % 1-bromo-2-chloropropane remaining. This oilwas then used directly in the next step.

EXAMPLE 8: PREPARATION OF1-{3-[4-(5-CHLORO-2-OXO-2,3-DIHYDRO-1H-1,3-BENZODIAZOL-1-YL)PIPERIDIN-1YL]PROPYL}-2,3-DIHYDRO(4,5,6,7-D4)-1H-1,3-BENZODIAZOL-2-ONE(COMPOUND 2)

A 0.5 L jacketed reactor equipped with a mechanical stirrer,thermocouple, and condenser under a nitrogen atmosphere was charged with5-chloro-1-(4-piperidyl)-1H-benzimidazol-2(3H)-one (Compound 14, 13.8 g,54.9 mmol, 1.0 eq), potassium iodide (9.1 g, 54.9 mmol, 1.0 eq),potassium bicarbonate (5.5 g, 54.9 mmol, 1.0 eq) and 60 mL of water. Tothis stirred suspension was charged a solution of 13.33 g (54.9 mmol,1.0 eq) of compound 16 in 60 mL of isopropanol. After heating to refluxwith a jacket temperature of 105° C. the reaction was stirred at thistemperature for 18 h until complete by HPLC analysis. An additional 30ml of water and 30 mL of isopropanol was added and reflux continued for20 min to dissolve solids, before adding 36 ml of 4M HCl (144 mmol, 2.6eq) to the refluxing mixture. Reflux was continued for 2 h until thedeprotection was complete. While still at reflux the batch was quenchedto pH 11 with 12 M sodium hydroxide. Product precipitation was observedand completed by cooling the batch to 15° C. and then collecting thesolid by vacuum filtration. The wet-cake was washed with water (3×51mL), then dried under vacuum to give 20.37 g (86.3%) of desired productwith 94.5% purity. Purity could be improved to >97% by recrystallizationfrom DMSO/water or trituration with IPA/water or MeOH/water.

The embodiments shown and described in the specification are onlyspecific embodiments of inventors who are skilled in the art and are notlimiting in any way. Therefore, various changes, modifications, oralterations to those embodiments may be made without departing from thespirit of the invention in the scope of the following claims. Each ofthe references cited are expressly incorporated by reference herein inits entirety.

What is claimed is:
 1. A composition comprising d₄-domperidone 2, or apharmaceutically acceptable salt thereof, and at least one excipient:


2. The composition of claim 1, comprising d₄-domperidone
 2. 3. A methodfor ameliorating a disorder that is gastroparesis, nausea apart fromgastroparesis, vomiting apart from gastroparesis, gastroesophagealreflux disease, nausea associated with gastroparesis, nausea apart fromgastroparesis, vomiting associated with gastroparesis, insufficientlactation, or a combination thereof in a patient, comprisingadministering to the patient the composition of claim
 1. 4. The methodof claim 3, wherein the administration ameliorates gastroparesis.
 5. Themethod of claim 3, wherein the administration ameliorates at least oneof nausea or vomiting as a separate disorder apart from nausea orvomiting as a result of gastroparesis in the patient.
 6. The method ofclaim 3, wherein the administration ameliorates insufficient lactation.7. A method for ameliorating a disorder that is gastroparesis, nauseaapart from gastroparesis, vomiting apart from gastroparesis,gastroesophageal reflux disease, nausea associated with gastroparesis,nausea apart from gastroparesis, vomiting associated with gastroparesis,insufficient lactation, or a combination thereof in a patient,comprising administering to the patient a therapeutically effectiveamount of a compound that is d₄-domperidone 2, or a pharmaceuticallyacceptable salt thereof:


8. The method of claim 7, wherein the therapeutically effective amountis in the range of 0.5 mg to 100 mg.
 9. The method of claim 7, whereinthe therapeutically effective amount is in the range of 1 mg to 60 mg.10. The method of claim 7, wherein the therapeutically effective amountis in the range of 2.0 mg to 30 mg.
 11. The method of claim 7, whereinthe therapeutically effective amount is in the range of 0.07 mg/kg to1.43 mg/kg.
 12. The method of claim 7, wherein the therapeuticallyeffective amount of is in the range of 0.014 mg/kg to 0.86 mg/kg. 13.The method of claim 7, wherein the amount is in the range of 0.028 mg/kgto 0.43 mg/kg.
 14. The method of claim 7, wherein the administrationameliorates gastroparesis.
 15. The method of claim 7, wherein theadministration ameliorates at least one of nausea or vomiting as aseparate disorder apart from nausea or vomiting as a result ofgastroparesis in the patient.
 16. The method of claim 7, wherein theadministration ameliorates insufficient lactation.